記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

Nonsense-mediated mRNA decay represents a biologic clearing system against aberrant mRNAs harboring nonsense and frameshift mutations and depends on three factors, UPF1, UPF2, and UPF3 (UPF3A, UPF3B). While germline pathogenic variants of UPF3B and UPF2 are known to be associated with neurodevelopmental disorders, germline variants in UPF1 have not been reported, until date, as being associated with any human disorders. Herein, we report two unrelated patients with de novo UPF1 variants. Patient 1 was a 5-year-old girl with intellectual disabilities, frontal bossing, hypertelorism, high frontal hairline, and thin upper lip. Patient 2 was a 2-year-old female child with intellectual disabilities and similar features. Trio exome analysis revealed a de novo heterozygous variant in UPF1 in both the patients (Patient 1: NM_002911.4): c.949_951del, p.(Asp317del); Patient 2: c.1984G>A, p.(Asp662Asn)). We conducted experiments using Drosophila models to evaluate the functional relevance of these UPF1 variants. Enforced expression of the wild-type Upf1 allele under the control of the pan-neuronal nSyb-GAL4 driver caused mortality, mostly at the pupal stage, but still yielded adult flies. By contrast, expression of the Asp294del (Asp317del in humans) variant caused embryonic or early larval lethality and that of the Asp643Asn (Asp662Asn in humans) caused third instar larval lethality; neither produced pupa nor adult fly. Thus, the developmental defects caused by the variants, especially Asp294del, were more severe than those caused by the wild-type allele. These observations suggest that both variants are deleterious mutations. In conclusion, germline variants in UPF1 are associated with intellectual disabilities in humans.

DOI： 10.1016/j.ejmg.2024.104983

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The recognition of syndromic forms of cleft palate is important for condition-specific management. Here, we report a patient with cleft palate, congenital heart disease, intellectual disability, and café-au-lait spots who had a deletion of chromosome 15q14. The identification of the precise breakpoints using a Nanopore-based long-read sequencer showed that the deletion spanned MEIS2 and SPRED1 loci. Cleft palate and café-au-lait spots can be ascribed to MEIS2 and SPRED1, respectively. Patients with cleft palate and café-au-lait spots should be encouraged to undergo a detailed genomic evaluation, including screening for a 15q14 deletion, to enable appropriate anticipatory medico-surgical management and genetic counseling.

DOI： 10.1177/10556656231188205

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Bohring-Opitz syndrome (BOS) is a rare disease with a characteristic facial appearance and limb position. This report describes a case of BOS complicated by persistent pulmonary hypertension of the newborn (PPHN) and formation of abnormal alveoli that was confirmed by autopsy. A female neonate was born by cesarean section at 37 weeks and 2 days of gestation and found to have a nevus flammeus, exophthalmos, abnormal palate, retraction of the mandible, and a posture characteristic of BOS. The patients had severe PPHN requiring inhalation of nitric oxide. Genetic testing revealed a de novo frameshift variant in ASXL1. Autopsy revealed that the lung was at the saccular stage, equivalent to 28-34 weeks of gestation. This is the first report to present pathological evidence of immaturity of the lung that may be associated with PPHN in a patient with BOS caused by a variant in ASXL1.

DOI： 10.1016/j.ejmg.2024.104978

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cockayne syndrome (CS) is a rare autosomal recessive disorder caused by mutations in ERCC8 or ERCC6. Most pathogenic variants in ERCC8 are single nucleotide substitutions. Structural variants (SVs) have been reported in patients with ERCC8-related CS. However, comprehensive molecular detection, including SVs of ERCC8, in CS patients remains problematic. Herein, we present three Japanese patients with ERCC8-related CS in whom causative SVs were identified using whole-exome-based copy number variation (CNV) detection tools. One patient showed compound heterozygosity for a 259-kb deletion and a deletion of exon 4 which has previously been reported as an Asia-specific variant. The other two patients were homozygous for the same exon 4 deletion. The exon 4 deletion was detected only by the ExomeDepth software. Intrigued by the discrepancy in the detection capability of various tools for the SVs, we evaluated the analytic performance of four whole-exome-based CNV detection tools using an exome data set from 337 healthy individuals. A total of 1,278,141 exons were predicted as being affected by the 4 CNV tools. Interestingly 95.1% of these affected exons were detected by one tool alone. Thus, we expect that the use of multiple tools may improve the detection rate of SVs from aligned exome data.

DOI： 10.1038/s41598-024-70831-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Digital clubbing is characterized by bulbous enlargement of the terminal segments of the fingers. Hypotheses including hypoxia have been proposed for the pathogenesis of digital clubbing, but the exact pathogenesis of digital clubbing is still uncertain. Lysinuric protein intolerance (LPI) is caused by pathogenic variants in SLC7A7 and is often associated with interstitial lung disease. Previously two patients of LPI with digital clubbing but without hypoxia have been reported. It is unclear whether digital clubbing in LPI is secondary to hypoxia or directly related to SLC7A7 deficiency. Here we report a 6-year-old Japanese boy presented with digital clubbing without hypoxia. He had episodic vomiting, each episode consisting of a single vomiting event occurring once a month, and his growth had been delayed. He had interstitial lung disease and hepatomegaly. He had compound heterozygous pathogenic variants in the SLC7A7, leading to the diagnosis of LPI. Together with the two previously reported patients mentioned above, we conclude that digital clubbing can occur in the absence of hypoxia. Digital clubbing in the absence of hypoxia has been observed in two genetic disorders related to prostaglandin (PG) E2, HPGD and SLCO2A1. PGE2 synthesis is primarily regulated by the cyclooxygenase 2, which plays a critical role in the control of inflammation. A high urine PGE level in the patient was compatible with the notion that PGE2 production may be increased in LPI. The occurrence of digital clubbing in the absence of hypoxia in LPI patients with SLC7A7 may be attributed to the mechanism of increased PGE2 production.

DOI： 10.1016/j.ejmg.2024.104967

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

CCP110 (centriolar coiled coil protein 110, also known as CP110) is one of the essential proteins localized in the centrosome that plays critical roles in the regulation of the cell cycle and also in the initiation of ciliogenesis. So far, no human congenital disorders have been identified to be associated with pathogenic variants of CCP110. Mice with biallelic loss-of-function variants of Ccp110 (Ccp110-/-) are known to manifest multiple organ defects, including a small body size, polydactyly, omphalocele, congenital heart defects, cleft palate, short ribs, and a small thoracic cage, a pattern of abnormalities closely resembling that in "ciliopathies" in humans. Herein, we report a 7-month-old male infant who presented with growth failure and skeletal abnormalities, including a narrow thorax and severe brachydactyly. Trio exome analysis of the genomic DNA of the patient and his parents showed that the patient was a compound heterozygote for truncating variants of CCP110, including a frameshift variant NM_001323572.2:c.856_857del, p.(Val286Leufs*5) inherited from the father, and a nonsense variant NM_001323572.2:c.1129C>T, p.(Arg377*) inherited from the mother. The strikingly similar pattern of malformations between Ccp110-/- mice and the 7-month-old male infant reported herein carrying unequivocal truncating CCP110 variants strongly supports the contention that CCP110 is a novel disease-causative gene.

DOI： 10.1016/j.ejmg.2024.104955

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Congenital anomalies of the kidney and urinary tract (CAKUT) can be a part of the VACTERL association, which represents the non-random combination of the following congenital anomalies: vertebral anomalies, anal anomalies, cardiac anomalies, tracheal-esophageal anomalies, kidney anomalies, and limb anomalies. VACTERL association is generally considered to be a non-genetic condition. Exceptions include a patient with a heterozygous nonsense SALL4 variant and anal stenosis, tetralogy of Fallot, sacro-vertebral fusion, and radial and thumb anomalies. SALL4 encodes a transcription factor that plays a critical role in kidney morphogenesis. Here, we report a patient with VACTERL association and a heterozygous 128-kb deletion spanning SALL4 who presented with renal hypoplasia, radial and atrio-septal defects, and patent ductus arteriosus. The present report of SALL4 deletion, in addition to a previously reported patient with VACTERL association phenotype and SALL4 nonsense mutation, further supports the notion that SALL4 haploinsufficiency can lead to VACTERL association.

DOI： 10.1007/s00467-024-06306-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

WOREE syndrome is an early infantile epileptic encephalopathy characterized by drug-resistant seizures and severe psychomotor developmental delays. We report a case of a WWOX splice-site mutation with uniparental isodisomy. A 1-year and 7-month-old girl presented with nystagmus and epileptic seizures from early infancy, with no fixation or pursuit of vision. Physical examination revealed small deformities, such as swelling of both cheeks, folded fingers, rocking feet, and scoliosis. Brain imaging revealed slight hypoplasia of the cerebrum. Electroencephalogram showed focal paroxysmal discharges during the interictal phase of seizures. Vitamin B6 and zonisamide were administered for early infantile epileptic encephalopathy; however, the seizures were not relieved. Despite altering the type and dosage of antiepileptic drugs and ACTH therapy, the seizures were intractable. Whole-exome analysis revealed the homozygosity of WWOX(NM_016373.4):c.516+1G>A. The WWOX mRNA sequencing using peripheral blood RNA confirmed that exon 5 was homozygously deleted. Based on these results, the patient was diagnosed with WOREE syndrome at 5 months. The WWOX variant found in this study is novel and has never been reported before. WOREE syndrome being extremely rare, further case series and analyses of its pathophysiology are warranted.

DOI： 10.1002/ajmg.a.63575

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Sonic hedgehog signaling molecule (SHH) is a key molecule in the cilia-mediated signaling pathway and a critical morphogen in embryogenesis. The association between loss-of-function variants of SHH and holoprosencephaly is well established. In mice experiments, reduced or increased signaling of SHH have been shown to be associated with narrowing or excessive expansion of the facial midline, respectively. Herein, we report two unrelated patients with de novo truncating variants of SHH presenting with hypertelorism rather than hypotelorism. The first patient was a 13-year-old girl. Her facial features included hypertelorism, strabismus, telecanthus, malocclusion, frontal bossing, and wide widow's peak. She had borderline developmental delay and agenesis of the corpus callosum. She had a nonsense variant of SHH: Chr7(GRCh38):g.155802987C > T, NM_000193.4:c.1302G > A, p.(Trp434*). The second patient was a 25-year-old girl. Her facial features included hypertelorism and wide widow's peak. She had developmental delay and agenesis of the corpus callosum. She had a frameshift variant of SHH: Chr7(GRCh38):g.155803072_155803074delCGGinsT, NM_000193.4:c.1215_1217delCCGinsA, p.(Asp405Glufs*92). The hypertelorism phenotype contrasts sharply with the prototypical hypotelorism-holoprosencephaly phenotype associated with loss-of-function of SHH. We concluded that a subset of truncating variants of SHH could be associated with hypertelorism rather than hypotelorism.

DOI： 10.1002/ajmg.a.63614

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Pathogenic variants in WDR45 on chromosome Xp11 cause neurodegenerative disorder beta-propeller protein-associated neurodegeneration (BPAN). Currently, there is no effective therapy for BPAN. Here we report a 17-year-old female patient with BPAN and show that antisense oligonucleotide (ASO) was effective in vitro. The patient had developmental delay and later showed extrapyramidal signs since the age of 15 years. MRI findings showed iron deposition in the globus pallidus and substantia nigra on T2 MRI. Whole genome sequencing and RNA sequencing revealed generation of pseudoexon due to inclusion of intronic sequences triggered by an intronic variant that is remote from the exon-intron junction: WDR45 (OMIM #300526) chrX(GRCh37):g.48935143G > C, (NM_007075.4:c.235 + 159C > G). We recapitulated the exonization of intron sequences by a mini-gene assay and further sought antisense oligonucleotide that induce pseudoexon skipping using our recently developed, a dual fluorescent splicing reporter system that encodes two fluorescent proteins, mCherry, a transfection marker designed to facilitate evaluation of exon skipping and split eGFP, a splicing reaction marker. The results showed that the 24-base ASO was the strongest inducer of pseudoexon skipping. Our data presented here have provided supportive evidence for in vivo preclinical studies.

DOI： 10.1038/s41598-024-56704-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

MYCN, a member of the MYC proto-oncogene family, regulates cell growth and proliferation. Somatic mutations of MYCN are identified in various tumors, and germline loss-of-function variants are responsible for Feingold syndrome, characterized by microcephaly. In contrast, one megalencephalic patient with a gain-of-function variant in MYCN, p.Thr58Met, has been reported, and additional patients and pathophysiological analysis are required to establish the disease entity. Herein, we report two unrelated megalencephalic patients with polydactyly harboring MYCN variants of p.Pro60Leu and Thr58Met, along with the analysis of gain-of-function and loss-of-function Mycn mouse models. Functional analyses for MYCN-Pro60Leu and MYCN-Thr58Met revealed decreased phosphorylation at Thr58, which reduced protein degradation mediated by FBXW7 ubiquitin ligase. The gain-of-function mouse model recapitulated the human phenotypes of megalencephaly and polydactyly, while brain analyses revealed excess proliferation of intermediate neural precursors during neurogenesis, which we determined to be the pathomechanism underlying megalencephaly. Interestingly, the kidney and female reproductive tract exhibited overt morphological anomalies, possibly as a result of excess proliferation during organogenesis. In conclusion, we confirm an MYCN gain-of-function-induced megalencephaly-polydactyly syndrome, which shows a mirror phenotype of Feingold syndrome, and reveal that MYCN plays a crucial proliferative role, not only in the context of tumorigenesis, but also organogenesis.

DOI： 10.1016/j.xhgg.2023.100238

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

Oculofaciocardiodental syndrome is caused by variants in the BCL6 corepressor (BCOR) gene. We identified a novel heterozygous frameshift variant, NM_001123385.2(BCOR):c.2326del, that arose de novo in a Japanese girl with characteristic facial features, congenital heart disease, bilateral syndactyly of toes 2 and 3, congenital cataracts, dental abnormalities, and mild intellectual disability. Reports of BCOR variants are rare, and further case accumulation is warranted.

DOI： 10.1038/s41439-023-00244-x

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その他リンク： https://www.nature.com/articles/s41439-023-00244-x

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DExH-box helicases are involved in unwinding of RNA and DNA. Among the 16 DExH-box genes, monoallelic variants of DHX16, DHX30, DHX34, and DHX37 are known to be associated with neurodevelopmental disorders. In particular, DHX30 is well established as a causative gene for neurodevelopmental disorders. Germline variants of DHX9, the closest homolog of DHX30, have not been reported until now as being associated with congenital disorders in humans, except that one de novo heterozygous variant, p.(Arg1052Gln) of the gene was identified during comprehensive screening in a patient with autism; unfortunately, the phenotypic details of this individual are unknown. Herein, we report a patients with a heterozygous de novo missense variant, p.(Gly414Arg) of DHX9 who presented with a short stature, intellectual disability, and ventricular non-compaction cardiomyopathy. The variant was located in the glycine codon of the ATP-binding site, G-C-G-K-T. To assess the pathogenicity of these variants, we generated transgenic Drosophila lines expressing human wild-type and mutant DHX9 proteins: 1) the mutant proteins showed aberrant localization both in the nucleus and the cytoplasm; 2) ectopic expression of wild-type protein in the visual system led to the rough eye phenotype, whereas expression of the mutant proteins had minimal effect; 3) overexpression of the wild-type protein in the retina led to a reduction in axonal numbers, whereas expression of the mutant proteins had a less pronounced effect. Furthermore, in a gene-editing experiment of Dhx9 G416 to R416, corresponding to p.(Gly414Arg) in humans, heterozygous mice showed a reduced body size, reduced emotionality, and cardiac conduction abnormality. In conclusion, we established that heterozygosity for a loss-of-function variant of DHX9 can lead to a new neurodevelopmental disorder.

DOI： 10.1016/j.ejmg.2023.104804

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/cga.12506

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/cga.12500

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The CpG island flanking the promoter region of SNRPN on chromosome 15q11.2 contains CpG sites that are completely methylated in the maternally derived allele and unmethylated in the paternally derived allele. Both unmethylated and methylated alleles are observed in normal individuals. Only the methylated allele is observed in patients with Prader-Willi syndrome, whereas only the unmethylated allele is observed in those with Angelman syndrome. Hence, detection of aberrant methylation at the differentially methylated region is fundamental to the molecular diagnosis of Prader-Willi syndrome and Angelman syndromes. Traditionally, bisulfite treatment and methylation-sensitive restriction enzyme treatment or methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) have been used. We here developed a long-read sequencing assay that can distinguish methylated and unmethylated CpG sites at 15q11.2 by the difference in current intensity generated from nanopore reads. We successfully diagnosed 4 Prader-Willi syndrome patients and 3 Angelman syndrome patients by targeting differentially methylated regions. Concurrent copy number analysis, homozygosity analysis, and structural variant analysis also allowed us to precisely delineate the underlying pathogenic mechanisms, including gross deletion, uniparental heterodisomy, uniparental isodisomy, or imprinting defect. Furthermore, we showed allele-specific methylation in imprinting-related differentially methylated regions on chromosomes 6, 7, 11, 14, and 20 in a normal individual together with 4 Prader-Willi patients and 3 Angelman syndrome patients. Hence, presently reported method is likely to be applicable to the diagnosis of imprinting disorders other than Prader-Willi syndrome and Angelman syndrome as well.

DOI： 10.1016/j.ejmg.2022.104690

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Collapsin response mediator protein 2 (Crmp2) is an evolutionarily well-conserved tubulin-binding cytosolic protein that plays critical roles in the formation of neural circuitry in model organisms including zebrafish and rodents. No clinical evidence that CRMP2 variants are responsible for monogenic neurogenic disorders in humans presently exists. Here, we describe two patients with de novo non-synonymous variants (S14R and R565C) of CRMP2 and intellectual disability associated with hypoplasia of the corpus callosum. We further performed various functional assays of CRMP2 variants using zebrafish and zebrafish Crmp2 (abbreviated as z-CRMP2 hereafter) and an antisense morpholino oligonucleotide [AMO]-based experimental system in which crmp2-morphant zebrafish exhibit the ectopic positioning of caudal primary (CaP) motor neurons. Whereas the co-injection of wild-type z-CRMP2 mRNA suppressed the ectopic positioning of CaP motor neurons in Crmp2-morphant zebrafish, the co-injection of R566C or S15R, z-CRMP2, which corresponds to R565C and S14R of human CRMP2, failed to rescue the ectopic positioning. Transfection experiments of zebrafish or rat Crmp2 using plasmid vectors in HeLa cells, with or without a proteasome inhibitor, demonstrated that the expression levels of mutant Crmp2 protein encoded by R565C and S14R CRMP2 variants were decreased, presumably because of increased degradation by proteasomes. When we compared CRMP2-tubulin interactions using co-immunoprecipitation and cellular localization studies, the R565C and S14R mutations weakened the interactions. These results collectively suggest that the CRMP2 variants detected in the present study consistently led to the loss-of-function of CRMP2 protein and support the notion that pathogenic variants in CRMP2 can cause intellectual disabilities in humans.

DOI： 10.1093/hmg/ddac166

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

CTR9 is one of five genes that form the PAF1 complex, which binds to RNA polymerase II and plays critical roles in transcriptional elongation and transcription-coupled histone modifications including histones H3K4me3 and H3K36me3. In this study, de novo CTR9 non-synonymous variants (p.(Glu15Asp) and p.(Pro25Arg)) were detected in two unrelated patients with macrocephaly, motor delay, and intellectual disability. A pull-down assay showed that the mutant CTR9 proteins had stronger affinities to the PAF1 protein than the wild-type protein. Functional analyses using zebrafish showed that the knockout of the ctr9 gene caused motor defects and enlargement of the telencephalon, which is homologous to the mammalian cerebrum. The rescue experiment, in which the human CTR9 mutants were introduced into ctr9-knockout zebrafish, failed to maintain the swimming posture of the ctr9-knockout fish, suggesting that the human CTR9 mutant proteins do not function normally in vivo. In addition, the overexpression of human CTR9 mutant mRNA caused telencephalon enlargement in zebrafish larvae, suggesting that the human CTR9 mutant proteins interfered with normal endogenous CTR9 function. We concluded that the two missense variants in CTR9 (p.(Glu15Asp) and p.(Pro25Arg)) cause a new syndrome involving macrocephaly, motor delay and intellectual disability through the loss of the normal function of CTR9 and the inhibition of the normal intrinsic CTR9 function of the contralateral allele.

DOI： 10.1093/hmg/ddac136

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/rheumatology/keac130

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記述言語：英語  

When a de novo balanced reciprocal translocation is identified in patients with multiple congenital abnormalities, attempts are often made to infer the relationship between the phenotype of the patient and genes in the proximity of the breakpoint. Here, we report a patient with intellectual disability, atrial septal defect, syndactyly, and cleft lip and palate who had an "apparently balanced" de novo reciprocal translocation t(4:18)(q31;q11.2) as well as a 7-Mb cryptic deletion spanning the HOXD cluster on chromosome 2q31 that was unrelated to the reciprocal translocation. Further analysis using a nanopore long-read sequencer showed complex rearrangements on both derivative chromosomes 4 and 18 and the deleted chromosome 2. First, the TLL1 locus, which is associated with atrial septal defect, was disrupted by the rearrangement involving chromosome 4. Second, the deleted interval at 2q31 included the entire HOXD cluster, the deletion of which is known to cause toe syndactyly, and the DLX1 and DLX2 loci, which are responsible for cleft lip and palate. Among the haplo-sensitive genes within the deleted interval on 2q31, only the RAPGEF4 gene is known to be associated with an autistic phenotype. Hence, most of the clinical features of the patient could be ascribed to specific genomic rearrangements. We have shown the effectiveness of long-read sequencing in defining, in detail, the likely effects of an apparently balanced translocation and cryptic deletion. The results of the present analysis suggest the possibility of phenotypic prediction through a detailed analysis of structural abnormalities, including balanced translocations and deletions.

DOI： 10.1002/ajmg.a.62777

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Here, we report a Japanese patient with Simpson-Golabi-Behmel syndrome involving a de novo 240-kb deletion including a part of GPC3. The patient showed pre- and postnatal macrosomia associated with coarse face, macrocephaly, supernumerary nipples, and cryptorchidism and characteristically presented with precocious puberty, mostly evaluated as advanced pubertal age of 15 years at the chronological age of 11.5 years.

DOI： 10.1038/s41439-022-00196-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Oral-facial digital (OFD) syndrome is characterized by abnormalities of the face (hypertelorism and low set-ears), oral cavity (multiple frenula, lingual hamartoma, or lobulated tongue) and extremities (postaxial polydactyly). At least 19 genes have been implicated in the development of OFD syndrome. Herein, we report the case a 13-year-old patient with atrioventricular septal defect, moderate intellectual disability, epilepsy, and features of OFD, including multiple oral frenula, and postaxial polydactyly of the hands and feet. The patient had a de novo heterozygous variant in PRKACB: chr1(GRCh37):g.84700915T > C, c.1124T > C (NM_182948.4), p.(Phe375Ser). To date, four patients with pathogenic monoallelic variants in PRKACB have been reported, and the condition associated with these variants is referred to as Cardioacrofacial dysplasia-2 (CAFD2, MIM619143). Previously reported features of this condition include congenital heart disease (e.g., atrioventricular septal defect) and postaxial polydactyly, and two of the patients had multiple oral frenula. We suggest that a significant phenotypic overlap exists between CAFD2 and OFD syndrome, in that these patients especially share the features of postaxial polydactyly and multiple oral frenula. The phenotypic similarity between patients with CAFD2 and classic OFD syndrome with an OFD1 variant might be explained by the recent in vitro experimental finding that a protein kinase A subunit encoded by PRKACB directly phosphorylates the OFD1 protein. From the standpoint of genetic counseling, OFD syndrome type1, the prototypic form of OFD, exhibits an X-linked dominant inheritance pattern, whereas other forms of OFD syndrome exhibit an autosomal recessive inheritance pattern. Recognition of CAFD2 as a differential diagnosis or forme fruste of OFD syndrome suggests that an autosomal dominant pattern of inheritance should also be considered during genetic counseling.

DOI： 10.1016/j.ejmg.2022.104512

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Germline mutations of NF1 cause neurofibromatosis type 1 (NF1) through the activation of the RAS signaling pathway, and some NF1 patients develop malignant peripheral nerve sheath tumors (MPNSTs). Here, we established subclones of the human NF1-MPNST cell line sNF96.2 that manifest increased tumorigenic activity and increased phosphorylation of the protein kinases MEK and Akt relative to the parental cells. Genomic DNA sequencing identified 14 additional heterozygous mutations within the coding regions of 13 cancer- and other disease-related genes in these subclones. One of these genes, PTPN11, encodes SHP-2, and the forced expression of the identified G503V mutant of SHP-2 increased both tumorigenic activity and MEK phosphorylation in parental sNF96.2 cells, suggesting that the combination of PTPN11 and NF1 mutations induces the pathological activation of the RAS pathway. These effects of SHP-2 (G503V) were inhibited by the coexpression of the G370A mutant of BRAP, which was also detected in the highly malignant subclones, and this inhibition was accompanied by the calpain-dependent cleavage of SHP-2 (G503V). The cleavage of SHP-2 (G503V) and suppression of MEK phosphorylation mediated by BRAP (G370A) were not detected in NF1-intact (HeLa) cells. Tumor promotion by SHP-2 (G503V) and its suppression by BRAP (G370A) may serve as a basis for the development of new treatment strategies for NF1.

DOI： 10.3390/cancers14102377

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: To delineate the diagnostic efficacy of medical exome, whole exome, and whole genome sequencing according to primary symptoms, the contribution of small copy number variations, and the impact of molecular diagnosis on clinical management. STUDY DESIGN: This was a prospective study of 17 tertiary care centers in Japan, conducted between April 2019 and March 2021. Critically ill neonates and infants less than 6 months of age were recruited in neonatal intensive care units and in outpatient clinics. The subjects underwent medical exome, whole exome, or whole genome sequencing during the first tier of testing. Subjects with negative results after medical exome or whole exome sequencing subsequently underwent whole genome sequencing. The impact of molecular diagnosis on clinical management evaluated through contacting primary care physicians. RESULTS: Of the 85 subjects, 41 (48%) had positive results. Based on the primary symptoms, patients with metabolic phenotypes had the highest diagnostic yield (67%, 4/6 subjects), followed by renal (60%, 3/5 subjects), and neurological phenotypes (58%, 14/24 subjects). Among them, 4 patients had pathogenic small copy number variations identified using whole genome sequencing. In the 41 subjects with molecular diagnosis, 20/41 (49%) had change in the clinical management. CONCLUSIONS: Genome analysis for critically ill neonates and infants had a high diagnostic yield for metabolic, renal, and neurological phenotypes. Small copy number variations detected using whole genome sequencing contributed to the overall molecular diagnosis in 5% of all the subjects. The resulting molecular diagnoses had a significant impact on clinical management.

DOI： 10.1016/j.jpeds.2022.01.033

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Nuclear factor one A (NFIA) is a transcription factor that regulates the development of the central nervous system. Haploinsufficiency of the NFIA gene causes NFIA-related disorder, which includes brain abnormalities and intellectual disability, with or without urinary tract defects. Intragenic deletions, nonsense variants, frameshift variants, and missense variants in one allele of the NFIA gene have been reported to cause various neurological and urogenital symptoms. Here we report a 10-year-old male patient with developmental delay, coarctation of the aorta, and distinctive facial features. Exome analysis identified a rare de novo heterozygous missense variant p.Thr395Met in NFIA. We employed zebrafish as a model organism in our NFIA analysis and found that nfia-/- zebrafish initially showed a loss of commissural axons in the brain, and eventually underwent growth retardation resulting in premature death. Impairment of the commissural neurons in nfia-/- zebrafish embryos could be restored by the expression of wild-type human NFIA protein, but not of mutant human protein harboring the p.Thr395Met substitution, indicating that this variant affects the function of NFIA protein. Taken together, we suggest that the p.Thr395Met allele in the NFIA gene is relevant to the pathogenesis of NFIA-related disorder.

DOI： 10.1002/ajmg.a.62638

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/ajmg.a.62531

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Menke-Hennekam syndrome-1 (MKHK1) is a congenital disorder caused by the heterozygous variants in exon 30 or 31 of CREBBP (CREB binding protein) gene mapped on 16p13.3. It is characterized by psychomotor delay, variable impairment of intellectual disability (ID), feeding difficulty, autistic behavior, hearing impairment, short stature, microcephaly, and facial dysmorphisms. The CREBBP loss-of-function variants cause Rubinstein-Taybi syndrome-1 (RSTS1). The function of CREBBP leading to MKHK1 has not been clarified so far, and the phenotype of MKHK1 significantly differs from that of RSTS1. We examined six patients with de novo pathogenic variants affecting the last exon of CREBBP, and they shared the clinical features of MKHK1. This study revealed that one frameshift and three nonsense variants of CREBBP cause MKHK1, and inferred that the nonsense variants of the last exon could further help in the elucidation of the etiology of MKHK1.

DOI： 10.1002/ajmg.a.62533

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

KARS encodes lysyl-tRNA synthetase, which is essential for protein translation. KARS mutations sometimes cause impairment of cytoplasmic and mitochondrial protein synthesis, and sometimes lead to progressive leukodystrophies with mitochondrial signature and psychomotor regression, and follow a rapid regressive course to premature death. There has been no disease-modifying therapy beyond supportive treatment. We present a 5-year-old male patient with an asymmetrical leukodystrophy who showed overt evidence of mitochondrial dysfunction, including elevation of lactate on brain MR spectroscopy and low oxygen consumption rate in fibroblasts. We diagnosed this patient's condition as KARS-related leukodystrophy with cerebral calcification, congenital deafness, and evidence of mitochondrial dysfunction. We employed a ketogenic diet as well as multiple vitamin supplementation with the intention to alleviate mitochondrial dysfunction. The patient showed alleviation of his psychomotor regression and even partial restoration of his abilities within 4 months. This is an early report of a potential disease-modifying therapy for KARS-related progressive leukodystrophy without appreciable adverse effects.

DOI： 10.1055/s-0041-1732446

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Recently, an international randomized controlled clinical trial showed that patients with SARS-CoV-2 infection treated orally with the 3-chymotrypsin-like protease (3CLpro) inhibitor PF-07321332 within three days of symptom onset showed an 89% lower risk of COVID-19-related hospital admission/ death from any cause as compared with the patients who received placebo. Lending support to this critically important result of the aforementioned trial, we demonstrated in our study that patients infected with a SARS-Cov-2 sub-lineage (B.1.1.284) carrying the Pro108Ser mutation in 3CLpro tended to have a comparatively milder clinical course (i.e., a smaller proportion of patients required oxygen supplementation during the clinical course) than patients infected with the same sub-lineage of virus not carrying the mutation. Characterization of the mutant 3CLpro revealed that the Kcat/Km of the 3CLpro enzyme containing Ser108 was 58% lower than that of Pro108 3CLpro. Hydrogen/deuterium-exchange mass spectrometry (HDX-MS) revealed that the reduced activity was associated with structural perturbation surrounding the substrate-binding region of the enzyme, which is positioned behind and distant from the 108th amino acid residue. Our findings of the attenuated clinical course of COVID-19 in patients infected with SARS-CoV-2 strains with reduced 3CLpro enzymatic activity greatly endorses the promising result of the aforementioned clinical trial of the 3CLpro inhibitor.

DOI： 10.1038/s41598-022-05424-3

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記述言語：英語  

Copy number variations (CNVs) have been related to developmental and epileptic encephalopathy (DEE). The 2q24.3 region includes a cluster of genes for voltage-gated sodium channels (SCN) and CNVs in this region cause DEE. However, the long-term course of DEE with a 2q24.3 duplication has not been described. A 20-year-old female developed epileptic encephalopathy in early infancy that was resistant to various antiseizure medications. Her seizures disappeared after starting vitamin B6 therapy. Therefore, her epilepsy was considered pyridoxine-dependent epilepsy. At 16 years old, whole exome sequencing revealed a 2q24.3 microduplication including SCN1A, SCN2A, SCN3A, SCN7A, and SCN9A. Quantitative PCR detected an increased copy number of 1.3 Mb on 2q24.3 involving these genes, but no gene mutation accounting for pyridoxine-dependent epilepsy. Considering that with this duplication she was reported to be seizure-free after infancy, she was able to be off antiseizure medications including vitamin B6. Our case involvingdrug-resistant epilepsy in early infancy had no recurrent seizures during long-term follow up. Detecting CNVs using whole exome sequencing data was useful to identify a 2q24.3 duplication unassociated with pyridoxine-dependent epilepsy, leading to cessation of unnecessary medications.

DOI： 10.1016/j.ebr.2022.100547

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記述言語：日本語   出版者・発行元：(一社)日本小児栄養消化器肝臓学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.seizure.2021.05.016

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Nuclear factor I A (NFIA) is a transcription factor that belongs to the NFI family. Truncating variants or intragenic deletion of the NFIA gene are known to cause the human neurodevelopmental disorder known as NFIA-related disorder, but no patient heterozygous for a missense mutation has been reported. Here, we document two unrelated patients with typical phenotypic features of the NFIA-related disorder who shared a missense variant p.Lys125Glu (K125E) in the NFIA gene. Patient 1 was a 6-year-old female with global developmental delay, corpus callosum anomaly, macrocephaly, and dysmorphic facial features. Patient 2 was a 14-month-old male with corpus callosum anomaly and macrocephaly. By using Drosophila and zebrafish models, we functionally evaluated the effect of the K125E substitution. Ectopic expression of wild-type human NFIA in Drosophila caused developmental defects such as eye malformation and premature death, while that of human NFIA K125E variant allele did not. nfia-deficient zebrafish embryos showed defects of midline-crossing axons in the midbrain/hindbrain boundary. This impairment of commissural neurons was rescued by expression of wild-type human NFIA, but not by that of mutant variant harboring K125E substitution. In accordance with these in vivo functional analyses, we showed that the K125E mutation impaired the transcriptional regulation of HES1 promoter in cultured cells. Taken together, we concluded that the K125E variant in the NFIA gene is a loss-of-function mutation.

DOI： 10.1002/ajmg.a.62226

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Craniosynostosis is caused by abnormalities of multiple signaling pathways, including excessive RAS signaling. Recently, a truncating variant in ETS2 repressor factor (ERF), a negative transcriptional regulator of the RAS pathway, was shown to be associated with craniosynostosis. Here, we report a 10-year-old male patient with a heterozygous nonsense mutation, p.Arg183*, in ERF who exhibited craniosynostosis with Noonan syndrome-like phenotypes. In consideration that loss-of-function variants in ERF would result in excessive RAS signaling and RASopathy phenotypes, we propose that ERF may represent a causative gene for Noonan syndrome. Since preceding studies on ERF mutations dealt with patients who were ascertained because of craniosynostosis, further studies are needed to evaluate whether patients with variants in ERF can present with Noonan syndrome-like features without craniosynostosis.

DOI： 10.1111/cga.12435

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

SARS-CoV-2 whole-genome sequencing of samples from COVID-19 patients is useful for informing infection control. Datasets of these genomes assembled from multiple hospitals can give critical clues to regional or national trends in infection. Herein, we report a lineage summary based on data collected from hospitals located in the Tokyo metropolitan area. We performed SARS-CoV-2 whole-genome sequencing of specimens from 198 patients with COVID-19 at 13 collaborating hospitals located in the Kanto region. Phylogenetic analysis and fingerprinting of the nucleotide substitutions were performed to differentiate and classify the viral lineages. More than 90% of the identified strains belonged to Clade 20B, which has been prevalent in European countries since March 2020. Only two lineages (B.1.1.284 and B.1.1.214) were found to be predominant in Japan. However, one sample from a COVID-19 patient admitted to a hospital in the Kanto region in November 2020 belonged to the B.1.346 lineage of Clade 20C, which has been prevalent in the western United States since November 2020. The patient had no history of overseas travel or any known contact with anyone who had travelled abroad. Consequently, the Clade 20C strain belonging to the B.1.346 lineage appeared likely to have been imported from the western United States to Japan across the strict quarantine barrier. B.1.1.284 and B.1.1.214 lineages were found to be predominant in the Kanto region, but a single case of the B.1.346 lineage of clade 20C, probably imported from the western United States, was also identified. These results illustrate that a decentralized network of hospitals offers significant advantages as a highly responsive system for monitoring regional molecular epidemiologic trends.

DOI： 10.2302/kjm.2021-0005-OA

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Lessel et al. reported a novel neurodevelopmental disorder with severe motor impairment and absent language (NEDMIAL) in 12 individuals and identified six different de novo heterozygous missense variants in DHX30. The other clinical features included muscular hypotonia, feeding difficulties, brain anomalies, autistic features, sleep disturbances, and joint hypermobility. We report a Japanese adult with a novel missense variant and two girls with de novo missense variants in DHX30.

DOI： 10.1038/s41439-021-00155-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The ALF transcription factor paralogs, AFF1, AFF2, AFF3, and AFF4, are components of the transcriptional super elongation complex that regulates expression of genes involved in neurogenesis and development. We describe an autosomal dominant disorder associated with de novo missense variants in the degron of AFF3, a nine amino acid sequence important for its binding to ubiquitin ligase, or with de novo deletions of this region. The sixteen affected individuals we identified, along with two previously reported individuals, present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoe kidney, NS for Nievergelt/Savarirayan type of mesomelic dysplasia, S for seizures, H for hypertrichosis, I for intellectual disability, and P for pulmonary involvement), partially overlapping the AFF4-associated CHOPS syndrome. Whereas homozygous Aff3 knockout mice display skeletal anomalies, kidney defects, brain malformations, and neurological anomalies, knockin animals modeling one of the microdeletions and the most common of the missense variants identified in affected individuals presented with lower mesomelic limb deformities like KINSSHIP-affected individuals and early lethality, respectively. Overexpression of AFF3 in zebrafish resulted in body axis anomalies, providing some support for the pathological effect of increased amount of AFF3. The only partial phenotypic overlap of AFF3- and AFF4-associated syndromes and the previously published transcriptome analyses of ALF transcription factors suggest that these factors are not redundant and each contributes uniquely to proper development.

DOI： 10.1016/j.ajhg.2021.04.001

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記述言語：英語  

Some mammalian genes contain both major and minor introns, the splicing of which require distinctive major and minor spliceosomes, respectively; these genes are referred to as minor intron containing-genes. RNPC3 (RNA-binding domain-containing protein 3) is one of the proteins that are unique to the minor spliceosome U11/U12 di-snRNP. Only two families with biallelic pathogenic variants in the RNPC3 gene encoding the protein have been reported so far, and the affected members in both families had proportional short stature. While the affected members of the originally identified family did not have intellectual disability, the patients from the other family exhibited intellectual disability. Here, we report on a patient with severe primordial microcephalic dwarfism and intellectual disability who carried compound heterozygous variants in RNPC3 (NM_017619.3): c.261dup, p.Leu88Thrfs*11 and c.1228T>G, p.Phe410Val. The single nucleotide substitution c.1228T>G had a very high predictive score for pathogenicity: the p.Phe410 residue is highly conserved down to fish. Based on ACMG (American College of Medical Genetics and Genomics) guideline, this non-synonymous variant was scored as likely pathogenic. This documentation of yet another patient with biallelic RNPC3 variants exhibiting intellectual disability lends further support to the notion that intellectual disability is a key feature of the spectrum of RNPC3-related disorders.

DOI： 10.1002/ajmg.a.62152

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記述言語：英語  

Infantile liver failure syndrome type 1 (ILFS1) is a recently recognized autosomal recessive disorder caused by deleterious mutations in the leucyl-tRNA synthetase 1 gene (LARS1). The LARS1 enzyme is responsible for incorporation of the amino acid leucine during protein polypeptide synthesis. Individuals with LARS1 mutations typically show liver failure from infancy to early childhood during periods of illness or other physiological stress. While 25 patients from 15 families with ILFS1 have been reported in the literature, histological reports from autopsy findings are limited. We report here a premature male neonate who presented with severe intrauterine growth retardation, microcytic anemia, and fulminant liver failure, and who was a compound heterozygote for two novel deleterious mutations in LARS1. An autopsy showed fulminant hepatitis-like hepatocellular injury and fibrogenesis in the liver and a lack of uniformity in skeletal muscle, accompanied by the disruption of striated muscle fibers. Striking dysgenesis in skeletal muscle detected in the present case indicates the effect of LARS1 functional deficiency on the musculature. Whole-exome sequencing may be useful for neonates with unexplained early liver failure if extensive genetic and metabolic testing is inconclusive.

DOI： 10.1002/ajmg.a.62012

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Skeletal overgrowth accompanied by de novo heterozygous activating mutations in PDGFRB (platelet-derived growth factor receptor beta), that is, p.Pro584Arg and p.Trp566Arg, defines Kosaki overgrowth syndrome (OMIM #616592). Emerging evidence suggests a role of PDGFRB in the genesis of cerebral aneurysms. The delineation of the range and progression of the vascular phenotype of Kosaki overgrowth syndrome is urgently needed. Herein, we conducted subsequent analyses of serial neurovascular imaging studies of two original patients with a de novo heterozygous mutation in PDGFRB, that is, p.Pro584Arg. The analysis showed the progressive dilation of basilar and vertebral arteries and coronary arteries commencing during the teenage years and early 20s. The radiographic appearance of the basilar vertebral aneurysms showed signs of arterial wall dilation, compatible with the known vascular pathology of vascular-type Ehlers-Danlos syndrome and Loeys-Dietz syndrome. The dolichoectasia in cerebrovascular arteries can lead to fatal complications, even with neurosurgical interventions. To prevent the progression of artery dilation, preventative and therapeutic medical measures using tyrosine kinase inhibitors may be necessary in addition to optimal control of the systemic blood pressure. Kosaki overgrowth syndrome is a clinically recognizable syndrome that can exhibit progressive dilatory and tortuous vascular changes in basilar/vertebral and coronary arteries as early as in the teenage years. We recommend careful counseling regarding the risk of future vascular complications, optimal blood pressure control, and regular systemic vascular screening during follow-up examinations.

DOI： 10.1002/ajmg.a.62027

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記述言語：英語  

The LRP5 gene encodes a Wnt signaling receptor to which Wnt binds directly. In humans, pathogenic monoallelic variants in LRP5 have been associated with increased bone density and exudative vitreoretinopathy. In mice, LRP5 plays a role in tooth development, including periodontal tissue stability and cementum formation. Here, we report a 14-year-old patient with a de novo non-synonymous variant, p.(Val1245Met), in LRP5 who exhibited mildly reduced bone density and mild exudative vitreoretinopathy together with a previously unreported phenotype consisting of dental abnormalities that included fork-like small incisors with short roots and an anterior open bite, molars with a single root, and severe taurodontism. In that exudative vitreoretinopathy has been reported to be associated with heterozygous loss-of-function variants of LRP5 and that our patient reported here with the p.(Val1245Met) variant had mild exudative vitreoretinopathy, the variant can be considered as an incomplete loss-of-function variant. Alternatively, the p.(Val1245Met) variant can be considered as exerting a dominant-negative effect, as no patients with truncating LRP5 variants and exudative vitreoretinopathy have been reported to exhibit dental anomalies. The documentation of dental anomalies in the presently reported patient strongly supports the notion that LRP5 plays a critical role in odontogenesis in humans, similar to its role in mice.

DOI： 10.1002/ajmg.a.62132

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Several studies have analyzed the long-term stability of cranioplasty and midface distraction in patients with craniosynostosis; however, few studies have investigated long-term quality of life (QOL) and complications in adults with syndromic craniosynostosis. This study aimed to investigate the QOL (social, physical, and psychosocial) of patients with adult syndromic craniosynostosis. Patients aged ≥20 years with syndromic craniosynostosis, who were surgically treated at a single craniofacial institution, were included in this study. We investigated everyday inconvenience (using the World Health Organization Disability Assessment Schedule questionnaire), any ongoing treatment, marital status, and number of children. Totally, 18 patients aged 22-48 years (mean: 31.4 ± 9.2 years) answered the questionnaire (Crouzon syndrome, 9; Apert syndrome, 5; Pfeiffer syndrome, 4). Of these, only one Crouzon syndrome patient was married; she was also the only one with a child. Apert syndrome patients were found to have difficulty in understanding, communication, and self-care because of their mental retardation and hand and foot handicaps; however, their participation in society was the most aggressive. In contrast, Crouzon syndrome patients had especially poor participation in society. In all patients, any ongoing hospital treatment was due to ophthalmological conditions. Crouzon syndrome patients have extremely poor QOL; the absence of mental retardation and hand and foot handicaps forces them to live in mainstream society, for which they are emotionally ill-equipped. It is necessary to treat these patients without any residual deformity to provide psychological support and to create an accepting society.

DOI： 10.1016/j.bjps.2020.08.102

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cortical dysplasia, complex, with other brain malformations 3 (CDCBM3) is a rare autosomal dominant syndrome caused by Kinesin family Member 2A (KIF2A) gene mutation. Patients with CDCBM3 exhibit posterior dominant agyria/pachygyria with severe motor dysfunction. Here, we report an 8-year-old boy with CDCBM3 showing a typical, but relatively mild, clinical presentation of CDCBM3 features. Whole-exome sequencing identified a heterozygous mutation of NM_001098511.2:c.1298C>A [p.(Ser433Tyr)]. To our knowledge, the mutation has never been reported previously. The variant was located distal to the nucleotide binding domain (NBD), in which previously-reported variants in CDCBM3 patients have been located. The computational structural analysis showed the p.433 forms the pocket with NBD. Variants in KIF2A have been reported in the NBD for CDCBM3, in the kinesin motor 3 domain, but not in the NBD in epilepsy, and outside of the kinesin motor domain in autism spectrum syndrome, respectively. Our patient has a variant, that is not in the NBD but at the pocket with the NBD, resulting in a clinical features of CDCBM3 with mild symptoms. The clinical findings of patients with KIF2A variants appear restricted to the central nervous system and facial anomalies. We can call this spectrum "KIF2A syndrome" with variable severity.

DOI： 10.1002/ajmg.a.62084

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGERNATURE  

Most patients with homozygous or compound heterozygous pathogenic ACO2 variants present with muscular hypotonia features, namely, infantile cerebellar-retinal degeneration. Recently, two studies reported rare familial cases of ACO2 variants presenting as complex hereditary spastic paraplegia (HSP) with broad clinical spectra. Here, we report the case of a 20-year-old Japanese woman with complex HSP caused by compound heterozygous ACO2 variants, revealing a new phenotype of episodic visual loss during febrile illness.

DOI： 10.1038/s41439-021-00136-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The third wave of the COVID-19 epidemic in the island of Hokkaido, the second largest island in Japan, began abruptly in October 2020. METHODS: We conducted a phylodynamic analysis of the SARS-CoV-2 genome sequences obtained from tertiary medical centers in the Greater Tokyo Area and Sapporo, the largest city in the island of Hokkaido, and genome sequences published by GISAID, an international SARS-CoV-2 genome database. We also analyzed the statistics on the person-nights of travelers in the island of Hokkaido from the Greater Tokyo Area in 2019 versus 2020. RESULTS: At least eight sub-lineages belonging to the B.1.1.214 lineage were introduced to the island of Hokkaido from the island of Honshu, the mainland of Japan from late July to November 2020, during the governmental travel promotion program. Five of the eight sub-lineages originated from the Greater Tokyo Area. Comparison of the monthly ratios of the person-nights of travelers in the island of Hokkaido from the Greater Tokyo Area in 2019 and 2020 revealed that the highest value occurred in October 2020. CONCLUSION: We contend that the Japanese governmental travel promotion program contributed to the introduction of the B.1.1.214 sub-lineages from the main island of Honshu to the island of Hokkaido, and drove the third wave in Hokkaido, even if we are unable to establish the causality.

DOI： 10.1016/j.tmaid.2021.102210

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記述言語：英語  

The heterozygous deletion of 15q13.3 is a recurrently observed microdeletion syndrome associated with a relatively mild phenotype including learning disability and language impairment. In contrast, the homozygous deletion of 15q13.3 is extremely rare and is associated with a much severer phenotype that includes epileptic encephalopathy, profound intellectual disability, and hypotonia. Which of the genes within the deleted interval is responsible for the more severe features when biallelically deleted is currently unknown. Here, we report a patient with profound hypotonia, severe intellectual disability, and seizures who had biallelic loss-of-function variants in OTUD7A: a 15q13.3 deletion including the OTUD7A locus, and a frameshift OTUD7A variant c.1125del, p.(Glu375Aspfs*11). Unexpectedly, both aberrations occurred de novo. Our experiment using Caenorhabditis elegans showed that worms carrying a corresponding homozygous variant in the homolog OTUB-2 exhibited weakened muscle contraction suggestive of aberrant neuromuscular transmission. We concluded that the biallelic complete loss of OTUD7A in humans represents a presumably new autosomal recessive disorder characterized by profound hypotonia, severe intellectual disability, and seizures.

DOI： 10.1002/ajmg.a.62054

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We report a male adult with early infantile-onset epilepsy, facial dysmorphism, and iridal and choroidal coloboma who had a de novo heterozygous mutation in PACS2, that is, c.625G > A p.(Glu209Lys). This specific mutation was previously reported in a patient with PACS2-related disorder (early infantile epileptic encephalopathy 66). De novo heterozygous mutations in WDR37 have been shown to cause a novel human disorder, neurooculocardiogenitourinary syndrome (NOCGUS syndrome) (OMIM #618652), characterized by intellectual disability, facial dysmorphism, and coloboma. According to large-scale interactome data, WDR37 interacts most strongly, by far, with PACS1 and PACS2. Clinically, coloboma has been described as a feature in a WDR37-related disorder and a PACS1-related disorder (Schuurs-Hoeijmakers syndrome), but not in a PACS2-related disorder. Our review of the phenotypes of three human disorders caused by WDR37, PACS1, and PACS2 mutations showed a significant overlap of epilepsy, intellectual disability, cerebellar atrophy, and facial features. The present observation of coloboma as a shared feature among these three disorders suggests that this group of genes may be involved in ocular development. We propose that dysregulation of the WDR37-PACS1-PACS2 axis results in a spectrum that is recognizable by intellectual disability, distinctive facial features, and coloboma.

DOI： 10.1002/ajmg.a.62020

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記述言語：英語  

BACKGROUND: Mutations in GNAO1 typically result in neurodevelopmental disorders, including involuntary movements. They may be improved using calcium-channel modulators. CASE: The patient visited our hospital at age 2 years because of moderate global developmental delay. Her intermittent, generalized involuntary movements started at age 8 years. A de novo GNAO1 mutation, NM_020988.2:c.626G > A, (p.Arg209Cys), was identified by whole exome sequencing. At age 9 years, she experienced severe, intermittent involuntary movements, which led to rhabdomyolysis. She needed intensive care with administration of midazolam, dantrolene sodium hydrate, and plasma exchange. We started treating her with gabapentin (GBP), after which she recovered completely. At age 11 years, she developed continuous, generalized involuntary movements. This prompted us to increase the GBP dose, which again resolved the involuntary movements completely. CONCLUSION: In the case of movement disorders associated with GNAO1 mutations, GBP treatment may be attempted before more invasive procedures are performed.

DOI： 10.1016/j.braindev.2020.12.002

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Chimeric transcripts are formed by chromosomal aberrations. Little is known about the role of chimeric transcripts in the pathogenesis of birth defects. We reanalyzed RNA-seq data in alignment map files from the peripheral blood of 56 patients in whom the diagnoses could not be confirmed by standard exome analysis and transcriptome analysis to screen for chimeric transcripts using a dedicated software, ChimPipe. Chimeric analysis led to a diagnosis in two of the 56 patients: 1) The first patient had a chimeric transcript spanning the causative gene ZEB2 and the GTDC1 gene in its neighboring locus. RNA-seq revealed reads spanning exon 5 of ZEB2 and exon 7 of GTDC1. Whole genome sequencing revealed a 436-kb deletion spanning intron 4 of ZEB2 and intron 7 of GTDC1 and the diagnosis of Mowat-Wilson syndrome was made. 2) The second patient had a chimeric transcript spanning the causative gene KCNK9 and the TRAPPC9 gene in its neighboring locus. RNA-seq revealed reads spanning exon 21 of TRAPPC9 and exon 1 of KCNK9. Whole genome sequencing revealed a 186-kb deletion spanning intron 20 of TRAPPC9 and intron 1 of KCNK9 in this patient. KCNK9 gene is a maternally expressed imprinted gene. The diagnosis of Birk-Barel syndrome was made. Thus, both patients had chimeric transcripts that were directly involved in the pathogenesis of the birth defects. The approach reported herein, of detecting chimeric transcripts from RNA-seq data, is unique in that the approach does not rely on any prior information on the presence of genomic deletion. This article is protected by copyright. All rights reserved.

DOI： 10.1111/cga.12400

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

COVID-19 caused by SARS-CoV-2 is a worldwide problem. From the standpoint of hospital infection control, determining the source of infection is critical. We conducted the present study to evaluate the efficacy of using whole genome sequencing to determine the source of infection in hospitalized patients who do not have a clear infectious contact history. Recently, we encountered two seemingly separate COVID-19 clusters in a tertiary hospital. Whole viral genome sequencing distinguished the two clusters according to the viral haplotype. However, the source of infection was unclear in 14 patients with COVID-19 who were clinically unlinked to clusters #1 or #2. These patients, who had no clear history of infectious contact within the hospital ("undetermined source of infection"), had haplotypes similar to those in cluster #2 but did not have two of the mutations used to characterize cluster #2, suggesting that these 14 cases of "undetermined source of infection" were not derived from cluster #2. Whole viral genome sequencing can be useful for confirming that sporadic COVID-19 cases with an undetermined source of infection are indeed not part of clusters at the institutional level.

DOI： 10.1016/j.jhin.2020.10.014

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cyclin-dependent kinase 8 (CDK8) is a member of the CDK/Cyclin module of the mediator complex. A recent study reported that heterozygous missense CDK8 mutations cause a neurodevelopmental disorder in humans. The mechanistic basis of CDK8-related disorder has yet to be delineated. Here, we report 2 patients with de novo missense mutations within the kinase domain of CDK8 along with the results of in vitro and in vivo functional analyses using a zebrafish model. Patient 1 and Patient 2 had intellectual disabilities and congenital anomalies. Exome analyses showed that patient 1 had a heterozygous de novo missense p.G28A variant in the CDK8 (NM_001260.3) gene and patient 2 had a heterozygous de novo missense p.N156S variant in the CDK8 gene. We assessed the pathogenicity of these two variants using cultured-cells and zebrafish model. An in vitro kinase assay of human CDK8 showed that enzymes with a p.G28A or p.N156S substitution showed decreased kinase activity. An in vivo assays of zebrafish overexpression analyses also showed that the p.G28A and p.N156S alleles were hypomorphic alleles. Importantly, the inhibition of CDK8 kinase activity in zebrafish embryos using a specific chemical inhibitor induced craniofacial and heart defects similar to the patients' phenotype. Taken together, zebrafish studies showed that non-synonymous variants in the kinase domain of CDK8 act as hypomorphic alleles causing human congenital disorder.

DOI： 10.1038/s41598-020-74642-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension that is usually difficult to diagnose and is refractory to conservative treatment. PVOD can occur in connection with high-dose chemotherapy or hematopoietic stem cell transplantation, similar to hepatic veno-occlusive disease (HVOD). Here, we present a case of neuroblastoma with PVOD following HVOD after high-dose chemotherapy that was resolved with conservative treatment. Respiratory symptoms or edema after HVOD may suggest PVOD, and prompt diagnosis on high-resolution computed tomography will result in a favorable prognosis.

DOI： 10.1097/MPH.0000000000001566

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記述言語：英語  

DOI： 10.1002/ajmg.a.61892

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: A weakness of exome analysis lies in inability to characterize aberrant splicing other than those involving consensus donor-acceptor sequence. To overcome this limitation, we developed a novel analytic method SAVNet that combines transcriptome and exome analysis which enabled the successful detection of carriers of splicing variants in the disease-causing genes of autosomal recessive disorders within a normal cohort. However, the clinical utility of the SAVNet analysis in delineating splicing defects in patients without a diagnosis has yet to be documented. METHOD: We performed SAVNet analysis using the integrated analysis of exome and transcriptome analysis from the peripheral blood of the patient. The patient is an undiagnosed Japanese female patient with submucous cleft palate, scaphocephaly and intellectual disability with no words at 8 years of age. Dysmorphic features included a long face, a short palpebral fissure, thick lips with an open month, premaxillary hypoplasia, a depressed nasal bridge, and satyr ears. RESULT: A SAVNet analysis showed that a heterozygous intronic variant located at the -10 position of exon 5 of the HNRNPK gene on chromosome 9 created a new splice acceptor sequence "ag" and led to the incorporation of 9 intronic nucleotides into the coding sequence. The mutant protein would have three extra amino acid residues, Leu-Leu-Gln, inserted within the critical KH domain. The patient was diagnosed as having recently delineated Au-Kline syndrome, which is characterized by cleft palate, craniosynostosis, and intellectual disability. CONCLUSION: The successful molecular diagnosis of the presently reported patient illustrates the diagnostic utility of the SAVNet analysis as an innovative way of implementing an integrated exome-transcriptome analysis in clinical settings.

DOI： 10.1002/mgg3.1364

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記述言語：英語  

The PUF60 gene encodes a ubiquitously expressed essential splicing factor that is recruited to the U2snRNA complex. The complex binds to the 3' splice site of exons in specific target genes and regulates the inclusion or exclusion of such exons. Recently, pathogenic variants of PUF60 have been shown to cause a relatively specific and potentially recognizable pattern of malformation referred to as Verheij syndrome. Here, we report a 12-year-old female patient with a de novo mutation in PUF60 whose phenotype was representative of the milder end of the phenotypic spectrum of Verheij syndrome; the de novo mutation was a frameshift mutation p.(Ser558Cysfs*21) that resulted in the addition of 21 extra amino acids at the carboxy end of the protein. Among the frequent features of Verheij syndrome, the patient exhibited coloboma, cervical spinal segmentation defects, and borderline intellectual functioning, but lacked cardiac abnormalities, deafness, and urogenital abnormalities. The results of RNA analysis using peripheral blood showed the escape of the mutant allele from nonsense-mediated mRNA decay, possibly accounting for the mild phenotype in the presently reported patient. Based on our clinical observations, we inferred that two embryologic processes, closure of the ocular plate and cervical spinal segmentation, are particularly susceptible to deficient PUF60-mediated splicing regulation, compared with other embryogenetic processes leading to the central nervous system, heart, ear, and kidney.

DOI： 10.1002/ajmg.a.61816

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Copy number variants (CNVs) are significant causes of rare and undiagnosed diseases. Parallel detection of single nucleotide variants (SNVs) and CNVs with exome analysis, if feasible, would shorten the diagnostic closure in a timely manner. We validated such "parallel" approach through a cohort study of 791 undiagnosed patients. In addition to routine exome analysis, we applied an innovative algorithm EXCAVATOR2 which enhances sensitivity by paradoxically exploiting read depth data that covers nonexonic regions where baits were not originally intended to hybridize. About 48 patients had copy number variations, 42 deletions, and 6 duplications with a resolution of 0.51-14.7 mega base pairs. Importantly from a clinical standpoint, we identified three patients with "dual diagnosis" due to concurrent pathogenic CNV and SNV. We suggest "hitting two birds with one stone" approach to exome data is an efficient strategy in deciphering undiagnosed patients and may well be considered as a first-tier genetic test.

DOI： 10.1002/ajmg.a.61822

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1097/MPH.0000000000001834

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The utility of whole exome analysis has been extensively demonstrated in research settings, but its clinical utility as a first-tier genetic test has not been well documented from diagnostic and health economic standpoints in real-life clinical settings. We performed medical exome analyses focusing on a clinically interpretable portion of the genome (4,813 genes) as a first-tier genetic test for 360 consecutive patients visiting a genetics clinic at a tertiary children's hospital in Japan, over a 3-year period. Bioinformatics analyses were conducted using standard software. A molecular diagnosis was made in 171 patients involving a total of 107 causative genes. Among these 107 causative genes, 57 genes were classified as genes with potential organ-specific interventions and management strategies. Clinically relevant results were obtained in 26% of the total cohort and 54% of the patients with a definitive molecular diagnosis. Performing the medical exome analysis at the time of the initial visit to the tertiary center, rather than after visits to pertinent specialists, brain MRI examination, and G-banded chromosome testing, would have reduced the financial cost by 197 euros according to retrospective calculation under multiple assumption. The present study demonstrated a high diagnostic yield (47.5%) for singleton medical exome analysis as a first-tier test in a real-life setting. Medical exome analysis yielded clinically relevant information in a quarter of the total patient cohort. The application of genomic testing during the initial visit to a tertiary medical center could be a rational approach to the diagnosis of patients with suspected genetic disorders.

DOI： 10.1002/ajmg.a.61589

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Shwachman-Diamond syndrome characterized by metaphyseal dysplasia, pancreatic insufficiency, and pancytopenia is caused by biallelic mutations in SBDS. Gene conversion between SBDS and its pseudogene SBDSP1 is the major cause. Here, we report two unrelated patients with Shwachman-Diamond syndrome who were shown to be compound heterozygotes for relatively frequent pathogenic alleles (the 258+2T>C allele and another allele composed of 183-184TA>CT and 201A>G) using an established polymerase chain reaction sequencing assay with SBDS-specific primers. Exome analysis of the patients showed discrepant results: 258+2T>C with variant allele frequency around 0.85, and no variants detected for the 183-184TA>CT allele. Parental exome analysis of the two families further supported this notion. Confronted with two patients with an unexpected segregation pattern, we performed a transcriptome analysis of peripheral blood-derived mRNA to demonstrate that the results were compatible with those obtained using SBDS-specific PCR primers. Both alleles could be accounted for by gene conversion events. The diagnostic discrepancy can be accounted for by a decreased efficiency in the computational mapping of the reads with 183-184TA>CT and 201A>G to the reference sequence of the SBDS locus during exome analysis. This report highlights the pitfall of exome analysis for genes with pseudogenes, such as SBDS and the alternative use of RNA-seq is recommended to circumvent this problem.

DOI： 10.1002/ajmg.a.61598

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記述言語：英語  

We identified biallelic pathogenic mutations in the Lipolysis-stimulated lipoprotein receptor (LSR) gene in a patient with infantile intrahepatic cholestasis. We established that mutations in the LSR gene, which encodes a protein which is critical for the formation of tricellular tight junctions in the liver, are a novel cause of pediatric cholestasis.

DOI： 10.1016/j.jpeds.2020.01.064

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

We report a 7-year-old boy with infantile spasms caused by a novel mutation in the Aristaless-related homeobox (ARX) gene. He showed infantile spasms and hypsarrhythmia on electroencephalogram from early infancy. Brain MRI did not reveal severe malformation of the brain except mild hypoplasia of the corpus callosum. Two-fold adrenocorticotropic hormone (ACTH) therapy failed to control the seizures, and ketogenic diet therapy and multi-antiepileptic drug therapy were required as he showed intractable daily tonic-clonic seizures. Exome sequencing identified a hemizygous mutation in the ARX gene, NG_008281.1(ARX_v001):c.1448 + 1 G > A, chrX: 25025227 C > T (GRCh37). To our knowledge, this mutation has not been reported previously.

DOI： 10.1038/s41439-020-0094-2

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記述言語：英語  

DOI： 10.1002/ajmg.a.61373

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Specific classes of de novo heterozygous gain-of-function pathogenic variants of the PDGFRB (platelet-derived growth factor receptor-beta) cause a distinctive overgrowth syndrome, named the Kosaki overgrowth syndrome (KOGS) (OMIM #616592). Until now, six patients with this condition have been reported in the literature. In addition to skeletal overgrowth, these patients exhibit hyperelastic, translucent, and fragile skin, scoliosis, progressive loss of subcutaneous adipose tissue, skull deformity, infantile myofibromas, neuropsychiatric symptoms, and arachnoid cysts in the posterior fossa and periventricular white matter signal abnormalities on neuroimaging. This constellation of phenotypes clearly distinguishes KOGS from other PDGFRB-related disorders, including idiopathic basal ganglia calcification, infantile myofibroma, and Penttinen-type premature aging syndrome. From a molecular standpoint, PDGFRB is a dimeric receptor tyrosine kinase that plays critical roles in cell growth and tumorigenesis. The two known types of pathogenic variants (p.(Pro584Arg) and p.(Trp566Arg)) of the PDGFRB that cause KOGS are exclusively located in the juxtaglomerular domain that regulates autoactivation/inhibition of PDGFRB. In-vitro evidence suggests that p.(Pro584Arg) represents a gain-of-function pathogenic variant. Inhibition of PDGFRB activity using multi-kinase inhibitors appears to be a potentially promising therapeutic approach. Investigation of the molecular mechanisms underlying the pathogenesis of this disease using induced pluripotent stem cells is under way. Presence of skeletal overgrowth, distinctive facial features, characteristic hyperelastic and fragile skin, and cerebral white matter lesions with neuropsychiatric symptoms should prompt genetic analysis of the PDGFRB.

DOI： 10.1002/ajmg.c.31755

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Neurocutaneous disorders are caused by germline and/or somatic mutations and involve the integument and central nervous systems. Congenital melanocytic nevus syndrome is characterized by melanotic skin lesions caused by somatic mutations at codon 61 in NRAS. A large cutaneous lesion raises the risk of central nervous system involvement. We report an 8-year-old girl with a congenital giant pigmented nevus that covered almost her entire back. Despite the absence of any radiological evidence of intracranial melanosis, the patient exhibited progressive limb spasticity with preserved intellectual ability. An extensive genetic analysis identified a specific class of heterozygous germline mutation in SPAST, p.(Arg499His), which is responsible for hereditary spastic paraplegia with infantile onset. In addition, a known heterozygous somatic mutation in NRAS, p.(Gln61Lys) was detected in the cutaneous lesion. This observation recapitulates concomitant mosaicism and non-mosaicism within a single individual and suggests that the possibility of a dual genetic diagnosis should be considered when neurological decline is observed in a patient with a neurocutaneous disorder without any detectable intracranial lesions.

DOI： 10.1016/j.ejmg.2019.103803

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記述言語：英語  

We report a patient with autism and cleft lip and palate carrying a de novo heterozygous AUTS2 mutation, c.1464_1467del ACTC (p.Tyr488*). Although the causal relationship between cleft lip and palate and this mutation is unclear, this case report may expand the clinical phenotype of AUTS2 syndrome.

DOI： 10.1002/ccr3.2377

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

N-ethylmaleimide-sensitive factor (NSF) plays a critical role in intracellular vesicle transport, which is essential for neurotransmitter release. Herein, we, for the first time, document human monogenic disease phenotype of de novo pathogenic variants in NSF, that is, epileptic encephalopathy of early infantile onset. When expressed in the developing eye of Drosophila, the mutant NSF severely affected eye development, while the wild-type allele had no detectable effect under the same conditions. Our findings suggest that the two pathogenic variants exert a dominant negative effect. De novo heterozygous mutations in the NSF gene cause early infantile epileptic encephalopathy.

DOI： 10.1002/acn3.50917

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記述言語：英語  

DOI： 10.1002/ajmg.a.61356

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Activation of the RAS pathway through either the activation of genes that accelerate the pathway or the suppression of genes that inhibit the pathway leads to a group of disorders collectively referred to as RASopathies. The key molecules of the RAS pathway are KRAS, HRAS, and NRAS. Mutations in these three RAS homolog genes have been shown to be associated with RASopathies. Recently, two patients with a Noonan syndrome phenotype were shown to carry mutations in the yet another RASopathy gene, MRAS (muscle RAS oncogene homolog). Here, we report a patient with a severe Noonan syndrome phenotype associated with a germline Q71R MRAS variant, which represents a recurrent substitution in RAS homologs in various cancers. The patient's dysmorphic features included relative macrocephaly, a down-slanted palpebral fissure, hypertelorism, a depressed nasal bridge, and low-set ears with thick lobes; these facial features are strongly associated with RASopathy. We confirmed that the MRAS gene represents a causative gene for RASopathy.

DOI： 10.1002/ajmg.a.61261

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/ajmg.a.61211

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cleft palate can be classified as either syndromic or nonsyndromic. SATB2-associated syndrome is one example of a syndromic cleft palate that is accompanied by intellectual disability, and various dental anomalies. SATB2-associated syndrome can be caused by several different molecular mechanisms including intragenic mutations and deletions of SATB2. Here, we report two patients with SATB2 truncating mutations (p.Arg239* and p.Asp702Thrfs*38) and one with a 4.4 megabase deletion including the SATB2 locus. All three patients had cleft palate and other dysmorphic features including macrodontia wide diastema. None of the three patients had acquired any meaningful words at the age of 5 years. In a review of the linguistic natural history of presently reported three patients and 30 previously reported patients, only two patients had attained verbal skills beyond speaking a few words. This degree of delayed speech contrasts with that observed in the prototypic form of syndromic cleft palate, 22q11.2 deletion syndrome. The recognition of SATB2-associated syndrome prior to palatoplasty would be important for plastic surgeons and the families of patients because precise diagnosis should provide predictive information regarding the future linguistic and intellectual abilities of the patients. Macrodontia with a wide diastema and cleft palate is a helpful and highly suggestive sign for the diagnosis of SATB2-associated syndrome.

DOI： 10.1002/ajmg.a.61114

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41439-019-0056-8.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：American Journal of Medical Genetics, Part A  

© 2019 Wiley Periodicals, Inc. Chromosome 12q15 microdeletion syndrome is characterized by intellectual disability and dysmorphic facial features, but the associations between each of the deleted genes and the phenotypes of 12q15 microdeletion syndrome remain unclear. Recently, the smallest region of overlap in 16 previously reported patients was used to define three candidate genes for the 12q15 microdeletion syndrome: CNOT2, KCNMB4, and PTPRB. Among these three candidate genes, CNOT2 maintains the structural integrity of the carbon catabolite repressor 4 (CCR4)-negative on TATA (NOT) complex, which plays a key role in regulating global gene expression, and is essential for the enzymatic activity of the CCR4-NOT complex. Disruption of the CCR4-NOT complex results in dysregulation of global gene expression, and is associated with various human disease processes, including neuronal diseases. Therefore, CNOT2 haploinsufficiency might account for the neurological features of the 12q15 microdeletion syndrome. Herein, we document a 12-year-old female patient with mild intellectual disability and multiple structural abnormalities including cleft lip and palate and 2–3 toe syndactyly.

DOI： 10.1002/ajmg.a.61068

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Schuurs-Hoeijmakers syndrome is a rare disease characterized by intellectual disability and dysmorphic facial features among various physical abnormalities due to PACS1 mutation. To date,<br />
28 patients with a recurrent de novo PACS1 mutation (c.607C &gt; T) have been reported, primarily<br />
in Western populations. Here, we describe two Japanese patients with Schuurs-Hoeijmakers<br />
syndrome with a recurrent PACS1 mutation. In addition to the typical clinical symptoms, each<br />
patient presented novel clinical phenotypes. One patient presented with involuntary movements<br />
and was treated with trihexyphenidyl hydrochloride. We hypothesized that the PACS1<br />
mutation leads to an inherent dopaminergic insufficiency that underlies the developing symptoms<br />
along with the neurodevelopmental processes. The second patient was diagnosed with<br />
lipomyelomeningocele during an examination for severe constipation at the age of 2 years and<br />
8 months. The diagnosis of lipomyelomeningocele in this patient was delayed due to the lack of<br />
cutaneous lesions. As the majority of patients with PACS1 mutation present constipation, underdiagnosis<br />
of lipomyelomeningocele is a possibility. As the phenotypic expansion of the patients<br />
with Schuurs-Hoeijmakers syndrome was not fully recognized, additional studies are needed to<br />
clarify the clinical spectrum.

DOI： 10.1002/ajmg.a.9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-019-40988-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Loss-of-function mutations in coagulation cascade proteins lead to bleeding diasthesis. In contrast, gain-of-function mutations in these proteins, which are exceptionally rare, lead to hereditary thrombosis. This is best exemplified by Factor V (i.e., Factor V Leiden) and Factor II (i.e., p.Arg596Leu). Here, we report a family with hereditary thrombosis. The proposita presented with cerebral venous thrombosis accompanied by infarction at the age of 12 years. Despite anticoagulation therapy with oral warfarin, she later developed deep venous thrombosis in her hepatic portal veins at the age of 27 years. A medical exome analysis identified a de novo heterozygous mutation p.Tyr434His in Factor II, which was segregated within the family. A retrospective molecular diagnosis was made using a preserved surgical specimen from the proposita's mother, who had died 10 years earlier. The p.Tyr434 residue, which was substituted in the presently reported family, was located in "exosite I" of thrombin, a critical recognition site for fibrinogen, protein C, and thrombin aptamer. Therefore, the mutant thrombin likely exerted its thrombophilic effect by altering the affinity of thrombin to downstream substrates. Furthermore, the "exosite I" domain of thrombin was inhibited by the arthropod bleeding toxin Triabin (a protein discovered from the saliva of the blood-sucking triatomine bug Triatoma pallidipennis). Our observation that patients with a p.Tyr434His mutation exhibited recurrent thrombosis provides the first proofof-concept in humans that a pharmacologic agent targeting "exosite I" could be an effective means of specifically modulating the thrombogenic-side of the coagulation system via the inhibition of factor II.

DOI： 10.1016/j.ejmg.2018.06.003

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：American Journal of Medical Genetics, Part A  

© 2018 Wiley Periodicals, Inc. The TWIST family is a group of highly conserved basic helix–loop–helix transcription factors. In humans, TWIST1 haploinsufficiency causes Saethre–Chotzen syndrome, which is characterized by craniosynostosis. Heterozygous localized TWIST1 and TWIST2 basic domain substitutions exert antimorphic effects to cause Sweeney–Cox syndrome, Barber–Say syndrome, and ablepharon-macrostomia syndrome, respectively. Sweeney–Cox syndrome, Barber–Say syndrome, and ablepharon-macrostomia syndrome share the facial features of ablepharon, hypertelorism, underdevelopment of the eyelids, and cheek pads adjacent to the corners of the mouth. Existence of phenotypic overlap between Saethre–Chotzen syndrome and Sweeney–Cox syndrome remains unknown. Herein, we document a male infant with the distinctive facial features of ablepharon, hypertelorism, cheek pads adjacent to the corners of the mouth, and bilateral coronal suture craniosynostosis who had a de novo heterozygous mutation in the basic domain of TWIST1, that is, c.351C&gt;G p.Glu117Asp. The pathogenicity of this variant was supported by in silico and in vivo evidence. Our review showed that Sweeney–Cox

DOI： 10.1002/ajmg.a.40525

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

<p>Nephronophthisis-related ciliopathies (NPHP-RC) are autosomal recessive disorders characterized by renal corticomedullary cysts with the extrarenal symptoms. Typically, patients with NPHP-RC reach end-stage kidney disease (ESKD) before the age of 30 years. We herein report a Japanese woman with NPHP-RC who had unusually delayed progression to ESKD after 6 decades. She exhibited liver dysfunction at the age of 23 years. She also showed mild renal dysfunction at the age of 43 years. Ultrasonography revealed bilateral multiple renal cysts with loss of corticomedullary differentiation. Her liver and renal functions gradually deteriorated. She was diagnosed with liver fibrosis as a result of biopsy, and initiated the maintenance hemodiafiltration therapy for ESKD at the age of 61 years. Because of a unique combination of multiple renal cysts and liver fibrosis, ciliopathy was suspected and medical exome analysis was performed. A novel homozygous missense mutation was identified in RPGRIP1L (c.1810G&gt;A p.Glu604Lys), a causative gene for NPHP-RC. To the best of our knowledge, this patient is the oldest one who progressed to ESKD in NPHP-RC. Our case illustrates that NPHP-RC should be included in the differential diagnosis of the patient with corticomedullary polycystic kidneys accompanied by the extrarenal organ involvements, even if the patient is elderly.</p>

DOI： 10.1159/000490770

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Neurofibromatosis type 1 (NF1) is caused by germline mutations in the NF1 gene and is characterized by café au lait spots and benign tumours known as neurofibromas. NF1 encodes the tumour suppressor protein neurofibromin, which negatively regulates the small GTPase Ras, with the constitutive activation of Ras signalling resulting from NF1 mutations being thought to underlie neurofibroma development. We previously showed that knockdown of neurofibromin triggers epithelial-mesenchymal transition (EMT) signalling and that such signalling is activated in NF1-associated neurofibromas. With the use of a cell-based drug screening assay, we have now identified the antiallergy drug tranilast (N-(3,4-dimethoxycinnamoyl) anthranilic acid) as an inhibitor of EMT and found that it attenuated the expression of mesenchymal markers and angiogenesis-related genes in NF1-mutated sNF96.2 cells and in neurofibroma cells from NF1 patients. Tranilast also suppressed the proliferation of neurofibromin-deficient cells in vitro more effectively than it did that of intact cells. In addition, tranilast inhibited sNF96.2 cell migration and proliferation in vivo. Knockdown of type III collagen (COL3A1) also suppressed the proliferation of neurofibroma cells, whereas expression of COL3A1 and SOX2 was increased in tranilast-resistant cells, suggesting that COL3A1 and the transcription factor SOX2 might contribute to the development of tranilast resistance.

DOI： 10.1038/s41598-018-24484-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Recently, in a cohort study with "overgrowth syndrome with intellectual disability," five subjects were reported to have de novo heterozygous truncating variants in HIST1H1E, which encodes linker histone H 1.4. However, their growth pattern appeared complex that four out of five patients had a decreasing height percentile over time, and three of these patients began with above-average heights but exhibited reductions to average heights or below when they were older. Herein, we report a female patient with intellectual disability and distinctive facial features including a wide nasal bridge and prominent cheek bones. She did not exhibit skeletal overgrowth, but she had a short stature at 21 years of age. An exome analysis identified a de novo heterozygous 1-bp duplication in HIST1H1E, that is, c.433dup p.(Ala145Glyfs*51). The physical features of the proposita were essentially the same as those observed in patients with the aforementioned HIST1H1E-related overgrowth syndrome. Our review of the growth trajectories in seven patients showed that five of seven patients did not exhibit skeletal overgrowth. This "lack of overgrowth in overgrowth syndrome" is reminiscent of a subset of patients with a short stature who have Sotos syndrome, a prototypic overgrowth syndrome. Considering this complexity in growth, this newly identified condition should be referred to as Rahman syndrome.

DOI： 10.1002/ajmg.a.38616

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Loss-of function mutations in NALCN on chromosome 13q, a sodium leak channel that maintains baseline neuronal excitability, cause infantile hypotonia with psychomotor retardation and characteristic faces 1 (IHPRF1, OMIM #615419). Here, we document two individuals with early onset hypotonia with poor feeding and intellectual disability who were compatible with a diagnosis of IHPRF1. The two patients had bi-allelic mutations in NALCN through two different genetic mechanisms: Patient 1 had bi-allelic splice site mutations, that is c.1267-2A>G, derived from heterozygous parents, while Patient 2 had a partial maternal uniparental isodisomy that harbored a frameshift mutation, that is c.2022_2023delAT, in chromosome 13 that was detected through a dedicated algorithm for homozygosity data mapping in whole exome sequencing. The delineation of the exact pattern of inheritance provided vital information regarding the risk of recurrence. In animal models with Nalcn mutations, two behavioral phenotypes, that are, postnatal dyspnea and sleep disturbance, have been reported. Our observations of the two patients with postnatal dyspnea and one patient with sleep disturbance support an association between these two behavioral phenotypes and NALCN mutations in humans. The routine use of a detection algorithm for homozygosity data mapping might improve the diagnostic yields of next-generation sequencing.

DOI： 10.1002/ajmg.a.38543

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

<p>Somatic truncating variants of the WAC gene have been observed in patients with hematologic malignancies. Furthermore, de novo heterozygous constitutional pathogenic variants of WAC have recently been shown to cause a syndromic form of intellectual disability, DeSanto-Shinawi syndrome. It is unknown whether the constitutional pathogenic variants observed in the intellectual disability syndrome overlap with the somatic pathogenic variants observed in hematologic abnormalities. Herein, we report three patients with constitutional truncating variants of WAC in an attempt to address the above questions. All three of the patients had mild to moderate intellectual disability and dysmorphic features. We then reviewed the phenotypic features of 19 patients with DeSanto-Shinawi syndrome, including the three currently reported ones: eight and seven patients showed a bulbous nasal tip and short fingers, respectively. As for the pathogenetic mechanism, we demonstrated that the expression level of the mRNA derived from the wildtype allele was higher than that derived from the mutated allele, demonstrating nonsense-mediated mRNA decay. This observation makes a haploinsufficiency mechanism likely. Reviews of the constitutional and somatic pathogenic variants observed in patients with hematologic malignancies showed a significant overlap of the two. To date, no patients with DeSanto-Shinawi syndrome have been reported to have developed hematologic abnormalities, except for one of the three patients reported herein who developed leukopenia and thrombocytopenia at the age of 19 years. Larger data sets are required to determine hematologic prognosis of patients with constitutional WAC variants.</p>

DOI： 10.1002/ajmg.a.38703

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

<p>Recently, 7 patients with de novo constitutional non-synonymous mutations in the CDK13 gene were ascertained through a trio exome analysis of a large cohort of 610 patients with congenital cardiac diseases. Despite another report describing 9 additional patients, the clinical spectrum of this condition has yet to be defined. Herein, we report 3 patients with heterozygous constitutional CDK13 mutations, who were ascertained through exome analysis of children with intellectual disability and minor anomalies, who lacked cardiac anomalies. Two patients had a c.2149G &gt; A, p.Gly717Arg mutation, and one had a c.2525A &gt; G, p. Asn842Ser mutation. A review of the previously described patients and those described herein has enabled the following points to be clarified. First, congenital heart diseases are not an essential feature (13/19). Second, nasal features may help syndromic recognition (14/16). Third, widely spaced and peg-shaped teeth may represent a previously unappreciated diagnostic clue for this newly identified syndrome. Here, we show that p.Gly717Arg represents a hotspot in addition to p.Asn842Ser. We suggest that this CDK13-related disorder may represent a clinically recognizable syndrome.</p>

DOI： 10.1016/j.ejmg.2017.12.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier B.V.  

Occipital lobe epilepsy of childhood includes two entities: Panayiotopoulos syndrome in pre-school children, and idiopathic childhood occipital epilepsy of Gastaut (ICOEG) in school-age children. The typical initial manifestation of the former is vomiting, and that of the latter is visual hallucinations. Ictal cardiopulmonary arrest at initial presentation has been reported for Panayiotopoulos syndrome, but not for ICOEG. We document a 7-year-old previously healthy girl who experienced an acute elemental visual hallucination of seeing insects, followed by a new-onset generalized seizure. Upon arrival at the local hospital, she was unconscious and soon thereafter, developed respiratory arrest. She was resuscitated and initiated on mechanical ventilation. An electroencephalogram taken three days after seizure cessation showed frequent occipital spikes, consistent with the diagnosis of ICOEG. The sequence of acute elementary visual hallucination followed by a motor seizure, and then witnessed respiratory arrest illustrated occurrence of life-threatening autonomic involvement at initial onset in ICOEG. We speculate that the epileptic propagation from the occipital lobes eventually compromised the respiratory center in the brainstem. The possibility of occipital lobe epilepsy should be considered in school-age children presenting with acute visual hallucination followed by respiratory arrest. Such a presentation should prompt an urgent electroencephalogram and initiation of antiepileptic treatment if indicated.

DOI： 10.1016/j.braindev.2017.06.009

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ejmg.2018.09.004.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/ajmg.a.40354.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1089/ther.2018.0019.

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記述言語：英語   出版者・発行元：WILEY  

DOI： 10.1002/humu.23307

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

<p>Wiedemann-Steiner syndrome (WDSTS) is an autosomal dominant disorder characterized by hypertrichosis, intellectual disability, and dysmorphic facial appearances (down-slanted vertically narrow palpebral fissures, wide nasal bridge, broad nasal tip, and thick eyebrows). In 2012, Jones and co-workers identified heterozygous mutations in KMT2A (lysine methyltransferase 2A) as the molecular cause of WDSTS. Although the phenotype of this syndrome continues to expand, the associated features are not fully understood. Here, we report WDSTS in a 12-year-old Japanese boy with a novel nonsense mutation in KMT2A. He had right preaxial polydactyly, which has not been previously reported in WDSTS. We could not identify a causal relationship between the KMT2A mutation and preaxial polydactyly, and cannot exclude the preaxial polydactyly is a simple coincidence. We summarized the clinical features of WDSTS associated with KMT2A mutation and discussed the cardinal symptoms in detail.</p>

DOI： 10.1002/ajmg.a.38405

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Heterozygous truncating mutations in ADNP are associated with a syndromic form of intellectual disability known as Helsmoortel-van der Aa syndrome. Among 17 previously reported patients with Helsmoortel-van der Aa syndrome, one patient exhibited blepharophimosis. Whether blepharophimosis represents a phenotypic expression of the ADNP mutation spectrum or a chance association remains unclear. Herein, we report another patient with a de novo truncating mutation in ADNP who exhibited a combination of blepharophimosis and epicanthal folds. In our retrospective re-evaluation of six originally reported patients whose facial photographs were available, at least one patient indeed had blepharophimosis and epicanthal folds. Furthermore, all three patients with blepharophimosis and epicanthal folds, including the presently reported patient, had truncating mutations at the same specific portion of the protein, that is the bipartite nuclear localization signal. Wesuggest that this specific class of ADNP mutation is likely associated with a blepharophimosis syndrome phenotype. From a clinical standpoint, a differential diagnosis of patients with blepharophimosis should include ADNP mutations in addition to blepharophimosis ptosis epicanthus inversus syndrome, especially when intellectual disability is present.

DOI： 10.1002/ajmg.a.38126

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：CELL PRESS  

Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define "YY1 syndrome" as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals' cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, these results define a clinical syndrome caused by haploinsufficiency of YY1 through dysregulation of key transcriptional regulators.

DOI： 10.1016/j.ajhg.2017.05.006

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記述言語：英語  

<p>The cover image, by Toshiki Takenouchi et al., is based on the Clinical Report Diagnostic use of computational retrotransposon detection: Successful definition of pathogenetic mechanism in a ciliopathy phenotype, DOI: 10.1002/ajmg.a.38167.</p>

DOI： 10.1002/ajmg.a.38263

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Among more than 5,000 human monogenic disorders with known causative genes, transposable element insertion of a Long Interspersed Nuclear Element 1 (LINE1, L1) is known as the mechanistic basis in only 13 genetic conditions. Meckel-Gruber syndrome is a rare ciliopathy characterized by occipital encephalocele and cystic kidney disease. Here, we document a boy with occipital encephalocele, post-axial polydactyly, and multicystic renal disease. A medical exome analysis detected a heterozygous frameshift mutation, c.4582_4583delCG p.(Arg1528Serfs*17) in CC2D2A in the maternally derived allele. The further use of a dedicated bioinformatics algorithm for detecting retrotransposon insertions led to the detection of an L1 insertion affecting exon 7 in the paternally derived allele. The complete sequencing and sequence homology analysis of the inserted L1 element showed that the L1 element was classified as L1HS (L1 human specific) and that the element had intact open reading frames in the two L1-encoded proteins. This observation ranks Meckel-Gruber syndrome as only the 14th disorder to be caused by an L1 insertion among more than 5,000 known human genetic disorders. Although a transposable element detection algorithm is not included in the current best-practice next-generation sequencing analysis, the present observation illustrates the utility of such an algorithm, which would require modest computational time and resources. Whether the seemingly infrequent recognition of L1 insertion in the pathogenesis of human genetic diseases might simply reflect a lack of appropriate detection methods remains to be seen.

DOI： 10.1002/ajmg.a.38167

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/ped.13216

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

<p>Therapeutic hypothermia is recommended for moderate and severe neonatal encephalopathy, but is being applied to a wider range of neonates than originally envisaged. To examine the clinical use of therapeutic hypothermia, data collected during the first 3 years (2012-2014) of the Baby Cooling Registry of Japan were analysed. Of 485 cooled neonates, 96.5% were =36 weeks gestation and 99.4% weighed =1,800 g. Severe acidosis (pH &lt; 7 or base deficit =16 mmol/L) was present in 68.9%, and 96.7% required resuscitation for &gt;10 min. Stage II/III encephalopathy was evident in 88.3%; hypotonia, seizures and abnormal amplitude-integrated electroencephalogram were observed in the majority of the remainder. In-hospital mortality was 2.7%; 90.7% were discharged home. Apgar scores and severity of acidosis/encephalopathy did not change over time. The time to reach the target temperature was shorter in 2014 than in 2012. The proportion undergoing whole-body cooling rose from 45.4% to 81.6%, while selective head cooling fell over time. Mortality, duration of mechanical ventilation and requirement for tube feeding at discharge remained unchanged. Adherence to standard cooling protocols was high throughout, with a consistent trend towards cooling being achieved more promptly. The mortality rate of cooled neonates was considerably lower than that reported in previous studies.</p>

DOI： 10.1038/srep39508

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記述言語：英語  

DOI： 10.1002/ajmg.a.38363

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/hgv.2017.33

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記述言語：英語  

<p>The cover image, by Toshiki Takenouchi et al., is based on the Clinical Report Hirschsprung disease as a yet undescribed phenotype in a patient with ARID1B mutation, DOI: 10.1002/ajmg.a.37861.</p>

DOI： 10.1002/ajmg.a.38046

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Mutations in the BAF complex (mammalian SWI/SNF complex) are responsible for Coffin-Siris syndrome, which is characterized by developmental delay, distinctive facial features, hirsutism, and hypoplasia/aplasia of the fifth finger/fingernails. Hirschsprung disease is characterized by defective stem cells in the enteric neural system, and the involvement of multiple signaling cascades has been implicated. So far, the roles of the BAF complex in the genesis of Hirschsprung disease have remained unknown. Here, we document a patient with coarse facial features, postnatal growth failure, developmental delay, epilepsy, and hypoplasia of the corpus callosum and cerebellum but without a hypoplastic fifth finger/fingernail. In addition, he had Hirschsprung disease. Exome sequencing with a gene set representing a total of 4,813 genes with known relationships to human diseases revealed a de novo heterozygous frameshift mutation in ARID1B (c.5789delC p.Pro1930Leufs*44). The presence of a congenital cataract and Hirschsprung disease in the presently reported patient further expands the phenotypic spectrum of patients with ARID1B mutations and may suggest the potential role of the BAF complex in the pathogenesis of the enteric neural system. The present observation is in agreement with a recent study of Drosophila neuroblasts showing that the dysregulated BAF complex leads to an abnormal lineage progression of neural stem cell lineages and that Hirschsprung disease is caused by abnormal stem cell lineages in the peripheral neural tissues. (C) 2016 Wiley Periodicals, Inc.

DOI： 10.1002/ajmg.a.37861

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/ajmg.a.37762

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Moyamoya disease is characterized by diffuse distal intracranial stenosis. Recently, RNF213 has been identified as a susceptibility gene in the development of this condition. Pulmonary hypertension is a rare progressive vasculopathy with an unknown etiology. The co-occurrence of pulmonary hypertension and Moyamoya disease has been described in four patients; however, whether this co-occurrence represents a chance association or a common vascular pathology has remained unknown. Here, we report two unrelated male patients who presented during their childhood with dyspnea on exertion. Systemic vascular imaging studies revealed the presence of pulmonary hypertension and Moyamoya disease in both patients. Medical exome sequencing revealed that both patients had a homozygous mutation for p.Arg4810Lys in RNF213. We suggest that homozygosity in RNF213 may lead to a novel entity involving the brain and lung. Interestingly, when present in a heterozygous state, this mutation causes a classic cerebral vascular disease, Moyamoya disease. In the homozygous state, the exact same mutation led to Moyamoya disease with extracranial systemic vasculopathy in at least two patients. From a clinical standpoint, cerebrovascular or pulmonary vascular investigations may be warranted in patients with pulmonary hypertension or Moyamoya disease, respectively. (C) 2016 Wiley Periodicals, Inc.

DOI： 10.1002/ajmg.a.37829

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

We previously documented a girl with macrothrombocytopenia and developmental delay who carried a de novo mutation in CDC42, which plays pivotal roles in the cell cycle and the formation of the actin cytoskeleton. The phenotype of mice lacking Cdc42 was strikingly similar to that of the reported patient, indicating that the mutation in CDC42 causes a new syndromic form of thrombocytopenia. We, herein, report another unrelated female patient with a similar phenotype and a de novo mutation in the same CDC42. The present observation provides further evidence supporting the notion that a mutation in CDC42 causes a recognizable syndromic form of thrombocytopenia. The cardinal features of this entity include macrothrombocytopenia, developmental delay, lymphedema in the lower extremities, camptodactyly, and distinctive facial features. (c) 2015 Wiley Periodicals, Inc.

DOI： 10.1002/ajmg.a.37526

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

&lt;p&gt;Sjögren syndrome is an autoimmune disease characterized by dry mouth and eyes, known as sicca symptoms. The exact spectrum of neurological involvement, especially of the central nervous system, in childhood Sjögren syndrome has not been well defined. We report a girl who presented with acute febrile brainstem encephalitis. In retrospect, she had exhibited a preceding history of recurrent conjunctivitis and strong halitosis that could be considered as sicca symptoms. The histopathology results of a minor salivary biopsy, the presence of anti-SSA/Ro antibody, and keratoconjunctivitis confirmed the diagnosis of Sjögren syndrome. Commonly observed features in previously reported patients with childhood Sjögren syndrome and central nervous system complications have included fever at the time of neurologic presentation, cerebrospinal fluid pleocytosis, abnormal neuroimaging, and positivity for several specific antibodies. In children presenting with unknown acute febrile encephalopathy, Sjögren syndrome should be included in the differential diagnosis, especially when sicca symptoms are present.&lt;/p&gt;

DOI： 10.1016/j.braindev.2015.05.005

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

<p>A recent study of exome analyses in 109 patients with undiagnosed diseases included a 5-year-old girl with intellectual disability and multiple congenital anomalies, who had an apparently de novo frameshift mutation in SON. However, the combination of the truncating mutation in SON and the phenotype has not been reproduced until date, and it remains unclear if this combination represents a distinctive disease entity. Here we report an additional male with intellectual disability, congenital heart disease, distinctive facial features with curly hair and protruding ears, and long slender extremities, and hyperextensible joints. Exome analysis showed that he had the same de novo frameshift mutation in SON in a heterozygous state. Along with the first and original description of the apparently de novo truncating mutation in SON mentioned above, we have established that haploinsufficiency of SON causes a new recognizable syndrome of intellectual disability. SON is located within 21q22.11, a critical region for Braddock-Carey syndrome, which is characterized by congenital thrombocytopenia, intellectual disability, micrognathia, and a distinctive facies. Therefore, we suggest that the intellectual disability observed in Braddock-Carey syndrome could be accounted for by haploinsufficiency of SON.</p>

DOI： 10.1002/ajmg.a.37761

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

The combinatory phenotype of thrombocytopenia and developmental delay has been described for two genetic conditions: a chromosome 11q deletion that is referred to as Jacobsen syndrome, and a 21q22 microdeletion syndrome. Herein, we report a young girl who presented with persistent macrothrombocytopenia and a developmental delay. Whole exome sequencing revealed a de novo amino acid substitution in CDC42, a critical regulator of the cytoskeleton. Our observation recapitulates observations in mice lacking Cdc42. We suggest that this CDC42 mutation may represent yet another mechanism leading to the combinatory phenotype of persistent macrothrombocytopenia and developmental delay. (c) 2015 Wiley Periodicals, Inc.

DOI： 10.1002/ajmg.a.37275

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Developmental Origins of Health and Disease theory stems from large-scale epidemiologic observation. The presumed mechanism for this hypothesis includes epigenetic changes; however, it remains to be elucidated if individuals with intrauterine growth retardation and epigenetic changes confirmed at the molecular level are indeed susceptible to adult-onset disease. Here we document three individuals with Russell-Silver syndrome, a prototypic condition caused by hypomethylation of the differently methylated imprinting center region 1 (ICR1) between the IGF2 and H19 loci on chromosome 11p15. At follow-up, the three patients developed adult-onset diseases such as obesity, hypertension, and diabetes mellitus in their early 20s. The presence of molecularly confirmed epigenetic changes in these patients provides a biological basis for Barker-Brenner's theory at an individual level.

DOI： 10.1111/cga.12105

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Although therapeutic hypothermia is known to improve neurologic outcomes after perinatal cerebral hypoxia-ischemia, etiology remains unknown. To decipher the mechanisms whereby hypothermia regulates metabolic dynamics in different brain regions, we used a two-step approach: a metabolomics to target metabolic pathways responding to cooling, and a quantitative imaging mass spectrometry to reveal spatial alterations in targeted metabolites in the brain. Seven-day postnatal rats underwent the permanent ligation of the left common carotid artery followed by exposure to 8% O-2 for 2.5 hours. The pups were returned to normoxic conditions at either 38 degrees C or 30 degrees C for 3 hours. The brain metabolic states were rapidly fixed using in situ freezing. The profiling of 107 metabolites showed that hypothermia diminishes the carbon biomass related to acetyl moieties, such as pyruvate and acetyl-CoA; conversely, it increases deacetylated metabolites, such as carnitine and choline. Quantitative imaging mass spectrometry demarcated that hypothermia diminishes the acetylcholine contents specifically in hippocampus and amygdala. Such decreases were associated with an inverse increase in carnitine in the same anatomic regions. These findings imply that hypothermia achieves its neuroprotective effects by mediating the cellular acetylation status through a coordinated suppression of acetyl-CoA, which resides in metabolic junctions of glycolysis, amino-acid catabolism, and ketolysis.

DOI： 10.1038/jcbfm.2014.253

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

DOI： 10.1002/ajmg.a.36947

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記述言語：日本語   出版者・発行元：日本レックリングハウゼン病学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE INC  

BACKGROUND: The juvenile form of GM1 gangliosidosis lacks specific physical findings and thus is often a diagnostic challenge for clinicians. T-2 hypodensity in the globus pallidus is a characteristic radiographic sign of neurodegeneration with iron accumulation in the brain that is observed in GM1 gangliosidosis, but the exact timing when this radiographic sign becomes apparent remains to be elucidated. PATIENTS: Two male siblings had normal development until 2 years of age and then developed psychomotor regression with dystonia. Their neuroimaging studies indicated progressive global cerebral atrophy. Exome sequencing identified compound heterozygous missense mutations in GLB1, leading to a diagnosis of GM1 gangliosidosis. RESULTS: A retrospective review of neuroimaging studies revealed that the two patients had strikingly similar clinical courses and radiographic progressions with cortical atrophy that preceded the T-2 hypointensity in the globus pallidus. CONCLUSIONS: Paramagnetic signals in the globus pallidus become apparent relatively late during the disease course, once cerebral atrophy has already become prominent. A comprehensive diagnostic approach involving clinical, radiographic, and genetic testing is necessary for the early identification of affected individuals.

DOI： 10.1016/j.pediatrneurol.2014.09.022

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MOSBY-ELSEVIER  

Using exome analysis, we identified a novel overgrowth syndrome arising from a mutation in PDGFRB, which plays a critical role in growth and differentiation. This entity is characterized by somatic overgrowth, distinctive facial features, hyperelastic and fragile skin, white matter lesions, and neurologic deterioration.

DOI： 10.1016/j.jpeds.2014.10.015

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

COL4A1-associated disorders encompass a wide range of hereditary vasculopathy, including porencephaly and HANAC (adult-onset hemorrhagic stroke with cerebral aneurysm and retinal arterial tortuosity, renal cysts, and thenar muscle cramp). It remains elusive whether or not porencephaly and HANAC are molecularly distinctive disorders due to different classes of mutations. We report on a girl with porencephaly and an episode of microangiopathic hemolysis in infancy and her father with HANAC, both of whom had a heterozygous missense mutation of COL4A1 (c.3715G&gt;A, p.G1239R). The current observation implies phenotypic diversities of COL4A1 mutations. (C) 2014 Wiley Periodicals, Inc.

DOI： 10.1002/ajmg.a.36823

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MARY ANN LIEBERT, INC  

Therapeutic hypothermia was first recommended as a standard of care by international guidelines in 2010. However, at that time, the number of centers capable of providing standard cooling was limited even in Japan. The aim of this project was to implement a nationwide network of evidence-based cooling within 3 years. A taskforce was formed in June 2010 to undergo the primary nationwide practice survey, design of action plans, and the appraisal of interventions by involving all registered level-II/III neonatal intensive care units in Japan. Based on findings from the primary survey, aggressive action plans were introduced that focused on the formulation of clinical recommendations, facilitation of educational events, and opening of an online case registry. Findings from the follow-up survey (January 2013) were compared with the results from the primary survey (June 2010). Four workshops and three consensus meetings were held to formulate clinical recommendations, which were followed by the publication of practical textbooks, large-scale education seminars, and implementation of a case registry. A follow-up survey covering 253 units (response rate: 89.1%) showed that cooling centers increased from 89 to 135. Twelve prefectures had no cooling centers in 2010, whereas all 47 prefectures had at least one in 2013. In cooling centers, adherence to the standard cooling protocols and the use of servo-controlled cooling devices improved from 20.7% to 94.7% and from 79.8% to 98.5%, respectively. A rapid improvement in the national provision of evidence-based cooling was achieved. International consensus guidelines coupled with domestic interventions might be effective in changing empirical approaches to evidence-based practice.

DOI： 10.1089/ther.2014.0015

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記述言語：英語  

We assessed the validity of a next-generation sequencing protocol using in-solution hybridization-based enrichment to identify NF1 mutations for the diagnosis of 86 patients with a prototypic genetic syndrome, neurofibromatosis type 1. In addition, other causative genes for classic genetic syndromes were set as the target genes for coverage analysis.<br />
The protocol identified 30 nonsense, 19 frameshift, and 8 splice-site mutations, together with 10 nucleotide substitutions that were previously reported to be pathogenic. In the remaining 19 samples, 10 had single-exon or multiple-exon deletions detected by a multiplex ligation-dependent probe amplification method and 3 had missense mutations that were not observed in the normal Japanese SNP database and were predicted to be pathogenic. Coverage analysis of the genes other than the NF1 gene included on the same diagnostic panel indicated that the mean coverage was 115-fold, a sufficient depth for mutation detection.<br />
The overall mutation detection rate using the currently reported method in 86 patients who met the clinical diagnostic criteria was 92.1% (70/76) when 10 patients with large deletions were excluded. The results validate the

DOI： 10.1089/gtmb.2014.0109

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MARY ANN LIEBERT, INC  

Aims: We assessed the validity of a next-generation sequencing protocol using in-solution hybridization-based enrichment to identify NF1 mutations for the diagnosis of 86 patients with a prototypic genetic syndrome, neurofibromatosis type 1. In addition, other causative genes for classic genetic syndromes were set as the target genes for coverage analysis. Results: The protocol identified 30 nonsense, 19 frameshift, and 8 splice-site mutations, together with 10 nucleotide substitutions that were previously reported to be pathogenic. In the remaining 19 samples, 10 had single-exon or multiple-exon deletions detected by a multiplex ligation-dependent probe amplification method and 3 had missense mutations that were not observed in the normal Japanese SNP database and were predicted to be pathogenic. Coverage analysis of the genes other than the NF1 gene included on the same diagnostic panel indicated that the mean coverage was 115-fold, a sufficient depth for mutation detection. Conclusions: The overall mutation detection rate using the currently reported method in 86 patients who met the clinical diagnostic criteria was 92.1% (70/76) when 10 patients with large deletions were excluded. The results validate the clinical utility of this next-generation sequencing-based method for the diagnosis of neurofibromatosis type 1. Comparable detection rates can be expected for other genetic syndromes, based on the results of the coverage analysis.

DOI： 10.1089/gtmb.2014.0109

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Dysregulation in the RAS signaling cascade results in a family of malformation syndromes called RASopathies. Meanwhile, alterations in FGFR signaling cascade are responsible for various syndromic forms of craniosynostosis. In general, the phenotypic spectra of RASopathies and craniosynostosis syndromes do not overlap. Recently, however, mutations in ERF, a downstream molecule of the RAS signaling cascade, have been identified as a cause of complex craniosynostosis, suggesting that the RAS and FGFR signaling pathways can interact in the pathogenesis of malformation syndromes. Here, we document a boy with short stature, developmental delay, and severe craniosynostosis involving right coronal, bilateral lambdoid, and sagittal sutures with a de novo mutation in exon1 of SHOC2 (c.4A&gt;G p.Ser2Gly). This observation further supports the existence of a crosslink between the RAS signaling cascade and craniosynostosis. In retrospect, the propositus had physical features suggestive of a dysregulated RAS signaling cascade, such as fetal pleural effusion, fetal hydrops, and atrial tachycardia. In addition to an abnormal cranial shape, which has been reported for this specific mutation, craniosynostosis might be a novel associated phenotype. In conclusion, the phenotypic combination of severe craniosynostosis and RASopathy features observed in the propositus suggests an interaction between the RAS and FGFR signaling cascades. Patients with craniosynostosis in combination with any RASopathy feature may require mutation screening for molecules in the FGFR-RAS signaling cascade. (c) 2014 Wiley Periodicals, Inc.

DOI： 10.1002/ajmg.a.36705

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記述言語：英語   出版者・発行元：WILEY-BLACKWELL  

DOI： 10.1002/ajmg.a.36671

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SAGE PUBLICATIONS INC  

Objective: Although cilostazol, a phosphodiesterase 3 inhibitor, has been suggested to strengthen the endothelial barrier using cultured endothelial monolayers, its effect has not been tested in vivo. We, therefore, investigated effects of cilostazol on barrier properties of postcapillary venules of the rat in situ.
Methods: Cilostazol was administered to the rats through oral gavage at 4 hours before the measurements. The hydraulic permeability (L-p) and the effective osmotic pressure (sigma Delta pi), molecular sieving properties of microvascular walls, were estimated in single mesenteric postcapillary venules by a micro-occlusion technique, first during control perfusion and then in the presence of histamine.
Results: When the vessels were inflamed with histamine, cilostazol attenuated a transient increase in L-p and prevented sigma Delta pi from falling. Furthermore, it reduced baseline L-p under a control state.
Conclusion: Cilostazol appears to tighten the endothelial barrier in situ, at least in part by inhibiting the cAMP-degrading enzyme in the endothelium.

DOI： 10.1177/0268355513497361

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1177/2333794X14550525

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BMJ PUBLISHING GROUP  

DOI： 10.1136/archdischild-2013-305807

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Cleidocranial dysplasia is a skeletal disorder characterized by a defective skull and defective clavicles caused by RUNX2, an activator of osteoblast differentiation. Consistent with the expression pattern of RUNX2, this disorder typically affects the skeletal system, but not the central nervous system. A 56-year-old man with the prototypic skeletal defects of cleidocranial dysplasia and a RUNX2 deletion presented with a progressive cognitive decline after the age of 40 years. After a failed cranioplasty during childhood, he had worn a protective helmet until young adulthood. His current neuroimaging studies revealed extensive cystic encephalomalacia beneath the defective skull, suggesting that his cognitive decline could likely be attributed to repetitive cerebral contusions. Late-onset progressive cognitive decline in the context of a defective skull accompanied by extensive cystic encephalomalacia illustrates the importance of natural calvarial protection against head injury. Since the majority of patients with cleidocranial dysplasia do not wear protective helmets beyond childhood, mainly for cosmetic reasons, a discussion of whether the social disadvantage outweighs the potential risk of brain parenchymal injury may be necessary. (C) 2014 Published by Elsevier Masson SAS.

DOI： 10.1016/j.ejmg.2014.04.015

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

The classification of bone dysplasia has relied on a clinical/radiographic interpretation and the identification of specific genetic alterations. The clinical presentation of the SOX9 mutation and type 2 collagen disorders overlap with the Pierre-Robin sequence and talipes equinovarus, but the former is often accompanied by the bent long bones. In its milder form, the SOX9 mutation is not necessarily associated with the bent long bones. Here, we report a patient with the Pierre-Robin sequence and talipes equinovarus who did not exhibit either bent long bones or scapular hypoplasia; thus, this patient was instead classified as having a type 2 collagen disorder. Despite this phenotypic presentation, the proposita was found to have a de novo SOX9 mutation. The peculiar location of the mutation within the dimerization domain might account for the relatively mild phenotypic effect of the SOX9 mutation to a degree that is compatible with a clinical diagnosis of type 2 collagen disorder, except for a developmental delay. We concluded that mutations in SOX9 can mimic a type 2 collagen disorder-like phenotype. (C) 2014 Published by Elsevier Masson SAS.

DOI： 10.1016/j.ejmg.2014.03.012

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Simpson-Golabi-Behmel syndrome is a rare overgrowth syndrome caused by the GPC3 mutation at Xq26 and is clinically characterized by multiple congenital abnormalities, intellectual disability, pre/postnatal overgrowth, distinctive craniofacial features, macrocephaly, and organomegaly. Although this syndrome is known to be associated with a risk for embryonal tumors, similar to other overgrowth syndromes, the pathogenetic basis of this mode of tumorigenesis remains largely unknown. Here, we report a boy with Simpson-Golabi-Behmel syndrome who had a germline loss-of function mutation in GPC3. At 9 months of age, he developed hepatoblastoma. A comparison of exome analysis results for the germline genome and for the tumor genome revealed a somatic mutation, p.Ile35Ser, within the degradation targeting box of -catenin. The same somatic mutation in CTNNB1 has been repeatedly reported in hepatoblastoma and other cancers. This finding suggested that the CTNNB1 mutation in the tumor tissue represents a driver mutation and that both the GPC3 and the CTNNB1 mutations contributed to tumorigenesis in a clearly defined sequential manner in the propositus. The current observation of a somatic CTNNB1 mutation in a hepatoblastoma from a patient with a germline GPC3 mutation supports the notion that the mutation in GPC3 may influence one of the initial steps in tumorigenesis and the progression to hepatoblastoma. (c) 2014 Wiley Periodicals, Inc.

DOI： 10.1002/ajmg.a.36364

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

&lt;p&gt;Recent advances in genetic diagnostic technologies have made the classic disease nosology highly complicated. This situation is exemplified by rasopathies, among which neurofibromatosis type 1 and Noonan syndrome represent prototypic entities. The former condition is characterized by multiple café au lait spots and neurofibromas, while the latter is characterized by distinct facial features, webbed neck, congenital heart disease, and a short stature. On rare occasions, the features of both neurofibromatosis and Noonan syndrome co-exist within an individual; such patients are diagnosed as having neurofibromatosis-Noonan syndrome. Here, we report familial patients with multiple café au lait spots and Noonan syndrome-like facial features. A mutation analysis unexpectedly revealed a mutation in MAP2K2 in both the propositus and his mother. The propositus fulfilled the diagnostic criteria for neurofibromatosis type 1, but his mother did not. Their phenotype was not consistent with that of cardio-facio-cutaneous syndrome, which is classically known to be associated with MAP2K2 mutations. The mother of the propositus had cervical cancer at the age of 23 years, consistent with the onc

DOI： 10.1002/ajmg.a.36288

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A growing body of evidence suggests an association between microdeletion/microduplication and schizophrenia/intellectual disability. Abnormal neurogenesis and neurotransmission have been implicated in the pathogenesis of these neuropsychiatric and neurodevelopmental disorders. The kainate/AMPA-type ionotropic glutamate receptor (GRIK=glutamate receptor, ionotropic, kainate) plays a critical role in synaptic potentiation, which is an essential process for learning and memory. Among the five known GRIK family members, haploinsufficiency of GRIK1, GRIK2, and GRIK4 are known to cause developmental delay, whereas the roles of GRIK3 and GRIK5 remain unknown. Herein, we report on a girl who presented with a severe developmental delay predominantly affecting her language and fine motor skills. She had a 2.6-Mb microdeletion in 1p34.3 involving GRIK3, which encodes a principal subunit of the kainate-type ionotropic glutamate receptor. Given its strong expression pattern in the central nervous system and the biological function of GRIK3 in presynaptic neurotransmission, the haploinsufficiency of GRIK3 is likely to be responsible for the severe developmental delay in the proposita. A review of genetic alterations and the phenotypic effects of all the GRIK family members support this hypothesis. The current observation of a microdeletion involving GRIK3, a kainate-type ionotropic glutamate receptor subunit, and the neurodevelopmental manifestation in the absence of major dysmorphism provides further clinical implication of the possible role of GRIK family glutamate receptors in the pathogenesis of developmental delay. © 2013 Wiley Periodicals, Inc.

DOI： 10.1002/ajmg.a.36240

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Recently, three marfanoid patients with congenital lipodystrophy and a neonatal progeroid appearance were reported. Although their phenotype was distinct from that of classic Marfan syndrome, they all had a truncating mutation in the penultimate exon, i.e., exon 64, of FBN1, the causative gene for Marfan syndrome. These patients might represent a new entity, but the exact phenotypic and genotypic spectrum remains unknown. Here, we report on a girl born prematurely who exhibited severe congenital lipodystrophy and a neonatal progeroid appearance. The patient exhibited a characteristic growth pattern consisting of an accelerated growth in height with a discrepant poor weight gain. She had a characteristic facial appearance with craniosynostosis. A mutation analysis identified c.8175_8182del8bp, p.Arg2726Glufs*9 in exon 64 of the FBN1 gene. A review of similar, recently reported patients revealed that the cardinal features of these patients include (1) congenital lipodystrophy, (2) premature birth with an accelerated linear growth disproportionate to the weight gain, and (3) a progeroid appearance with distinct facial features. Lines of molecular evidence suggested that this new progeroid syndrome represents a neomorphic phenotype caused by truncated transcripts with an extremely charged protein motif that escapes from nonsense-mediated mRNA decay, altering FBN1-TGF beta signaling, rather than representing the severe end of the hypomorphic phenotype of the FBN1-TGF beta disorder spectrum. We propose that this marfanoid entity comprised of congenital lipodystrophy, a neonatal progeroid appearance, and a peculiar growth profile and caused by rare mutations in the penultimate exon of FBN1, be newly referred to as marfanoid-progeroid syndrome. (c) 2013 Wiley Periodicals, Inc.

DOI： 10.1002/ajmg.a.36157

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

DOI： 10.1002/ajmg.a.35936

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Loeys-Dietz syndrome is a recently recognized connective tissue disorder characterized by severe craniofacial and skeletal abnormalities as well as arterial tortuosity with aggressive aneurysm formation. Marfan syndrome, a classic connective tissue disorder, is known to be associated with a risk of obstructive sleep apnea, but sleep-related breathing disorders have not been previously documented in Loeys-Dietz syndrome. The propositus had the prototypic features of Loeys-Dietz syndrome with a de novo mutation in TGFBR2. He developed severe obstructive sleep apnea during his infancy. Continuous positive airway pressure was introduced at age 7 years and provided significant improvement in his nocturnal apnea and sleep apnea-related symptoms, such as enuresis. Marfan syndrome is known to be associated with a high risk of sleep apnea because of its characteristic craniofacial and connective tissue abnormalities. Similarly, the severe craniofacial abnormalities in Loeys-Dietz syndrome may predispose patients to severe obstructive sleep apnea, even at a very young age. Despite the severity of obstructive sleep apnea in the propositus, the administration of continuous positive airway pressure was highly effective in alleviating his symptoms. In summary, severe obstructive sleep apnea was successfully treated using continuous positive airway pressure in a patient with Loeys-Dietz syndrome. Careful evaluation and aggressive intervention for the alleviation of obstructive sleep apnea is warranted in Loeys-Dietz syndrome. (c) 2013 Wiley Periodicals, Inc.

DOI： 10.1002/ajmg.a.35953

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Hypertension is one of the major complications in neurofibromatosis type 1 (NF1). It is known to be caused by renal artery stenosis or pheochromocytoma. However, more than half of hypertensive patients with NF1 do not have either disorder. We report here on a 13-year-old male with NF1 who had hypertension and a stenosis of the right renal artery associated with elevated renal vein renin on the diseased side. He underwent percutaneous transluminal renal angioplasty. In spite of successful dilation of the artery and normalized renin level, high blood pressure persisted beyond 6 months requiring antihypertensive medication. His wide pulse pressure suggested arterial stiffness due to NF1 vasculopathy. We posit that the cause of hypertension in this patient was considered to be arterial stiffness ascribed to NF1 vasculopathy rather than renal artery stenosis. Increased pulse pressure supports the hypothesis. This marker of arterial stiffness can be assessed non-invasively and should be evaluated routinely in NF1. (C) 2013 Wiley Periodicals, Inc.

DOI： 10.1002/ajmg.a.35829

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

BMP4 and OTX2 are master genes in ophthalmogenesis. Mutations of BMP4 and OTX2 often lead to eye defects, including anophthalmia-microphthalmia. A significant degree of variable expressivity has been reported in heterozygous individuals with BMP4 or OTX2 mutation. Interestingly, both BMP4 and OTX2 reside on 14q22, being only 2.8 Mb apart. Previous studies reported that among three patients with 14q22 deletion involving BMP4 and OTX2, all had severe eye defects. The minimal degree of variable expressivity among these individuals who were doubly deleted for BMP4 and OTX2 could be attributed to the combinatorial relationship of the two genes observed in animal models. We herein report a patient with a concurrent deletion of BMP4 and OTX2 who exhibited bilateral microphthalmia, more specifically, anterior segment dysgenesis with microcornea. Evolutionarily conserved physical linkage of Bmp4 and Otx2 loci may suggest an advantage of the proximal alignment of the two genes. Another striking feature in the propositus was the progressive white matter loss observed by serial neuroimaging. A review of twelve previously reported patients with 14q22 microdeletion revealed decreased white matter volume in half of the patients. It remains to be elucidated whether the white matter lesion is age-dependent and progressive. In conclusion, anterior segment defects of the eyes, especially when accompanied by decreased white matter volume on neuroimaging, should raise the clinical suspicion of 14q22 microdeletion. (c) 2012 Elsevier Masson SAS. All rights reserved.

DOI： 10.1016/j.ejmg.2012.10.007

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SAGE Publications Inc.  

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare motor neuron disease that can result in dysautonomia but is usually only mildly symptomatic. We report a young girl with SMARD1 who had a catastrophic autonomic crisis with resultant permanent brain damage during an interhospital transfer. Although she was only mildly symptomatic prior to the transfer, in retrospect, her baseline autonomic function analysis had sympathetic hyperactivity without a typical circadian rhythm, indicating the presence of severe underlying dysautonomia. Because this underlying dysautonomia seemed markedly aggravated by the psychological stress, careful autonomic evaluation and management are warranted in patients with SMARD1. © The Author(s) 2012.

DOI： 10.1177/0883073812453321

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記述言語：英語   出版者・発行元：ELSEVIER SCIENCE BV  

It has been recognized that gaseous molecules and their signaling cascades play a vital role in alterations of metabolic systems in physiologic and pathologic conditions. Contrary to this awareness, detailed mechanisms whereby gases exert their actions, in particular in vivo, have been unclear because of several reasons. Gaseous signaling involves diverse reactions with metal centers of metalloproteins and thiol modification of cysteine residues of proteins. Both the multiplicity of gas targets and the technical limitations in accessing local gas concentrations make dissection of exact actions of any gas mediator a challenge. However, a series of advanced technologies now offer ways to explore gas-responsive regulatory processes in vivo. Imaging mass spectrometry combined with quantitative metabolomics by capillary-electrophoresis/mass spectrometry reveals spatio-temporal profiles of many metabolites. Comparing the metabolic footprinting of murine samples with a targeted deletion of a specific gas-producing enzyme makes it possible to determine sites of actions of the gas. In this review, we intend to elaborate on the ideas how small gaseous molecules interact with metabolic systems to control organ functions such as cerebral vascular tone and energy metabolism in vivo. (C) 2012 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.resp.2012.03.016

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

The combination of holoprosencephaly and ectrodactyly, also known as Hartsfield syndrome, represents a unique genetic entity. An X-linked recessive mode of transmission has been suggested for this condition based on the observation that male patients have preferentially been affected. Thus far, no candidate genes have been suggested on the X chromosome. We report a male patient with a full-blown Hartsfield syndrome phenotype who had microduplication at Xq24 involving four genes. He presented with bilateral ectrodactyly of the hands (both hands had four fingers with a deep gap between the 2nd and 3rd digits), cleft lip and palate, and a depressed nasal bridge. Magnetic resonance imaging of the brain revealed lobar holoprosencephaly. His G-banded karyotype was normal. Array comparative genomic hybridization (CGH) using the Agilent 244K Whole Human Genome CGH array revealed a microduplication at Xq24 of 210 kb. Parental testing revealed that the deletion was derived from the asymptomatic mother. Of the genes on the duplicated interval, the duplications of SLC25A43 and SLC25A5 appeared to be the most likely to explain the patient's phenotype. From a clinical standpoint, it is important to point out that the propositus, who performs relatively well with holoprosencephaly and has a developmental quotient around 70, has survived multiple life-threatening episodes of hypernatremia. Awareness of the risk of hypernatremia is of great importance for the anticipatory management of patients with ectrodactyly and an oral cleft, even in the absence of overt hypotelorism. (C) 2012 Wiley Periodicals, Inc.

DOI： 10.1002/ajmg.a.35465

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

DOI： 10.1002/ajmg.a.35230

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Patients with 12q14 microdeletion can present with short stature with or without relative macrocephaly. When associated with relative macrocephaly, the phenotype resembles Silver-Russell syndrome (SRS). Short stature is attributable to haploinsufficiency of HMGA2, but a patient with a deletion at the HMGA2 locus only did not have macrocephaly. Hence, the presence of a separate locus for a relative macrocephaly phenotype was suggested. Herein, we present a girl with a 12q14 microdeletion involving the HMGA2 locus who had short stature but did not have macrocephaly. Inclusion and exclusion mappings based on a quantitative review of the degree of relative macrocephaly and the extent of the deletions in previously reported patients with a 12q14 microdeletion demonstrated a presumptive interval for relative macrocephaly spanning a few megabases. These results confirm that a deletion spanning both HMGA2 and this presumptive interval locus would cause an SRS-like phenotype. (C) 2012 Wiley Periodicals, Inc.

DOI： 10.1002/ajmg.a.35527

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Kabuki syndrome has long been clinically defined based mainly on its characteristic eye features. The recent discovery of MLL2 as a causative gene of Kabuki syndrome has enabled the extreme end of the phenotype to be explored. We herein report on two patients with striking visible congenital staphyloma at birth. A diagnosis of Kabuki syndrome was subsequently made in both patients based on a constellation of characteristic eye features, cardiac abnormalities and severe developmental delay, and finally by the confirmation of MLL2 mutations. In conclusion, congenital corneal staphyloma is a complication of Kabuki syndrome with MLL2 mutations. (C) 2012 Wiley Periodicals, Inc.

DOI： 10.1002/ajmg.a.35453

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Posterior cerebral artery (PCA) dissection in children seldom is reported in the literature. This is the second report of acute PCA dissection with infarct occurring in a young child. A serial magnetic resonance angiography demonstrated a delayed and transient narrowing of the arterial caliber, which was consistent with a focal PCA dissection with delayed vascular recanalization. PCA dissection should be included in the causes of infarct in children and a thorough and serial neurovascular imaging should be considered if no cause of stroke is found. (C) 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.braindev.2011.06.012

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Background: Therapeutic hypothermia is now recommended as a standard of care for neonatal encephalopathy. Although adherence to standard cooling protocols used in the phase-III trials is essential, empiric approaches have prevailed in Japan.
Aim: To elucidate the gap between the standard cooling methods and the current practice in Japan.
Method: In July 2010, a questionnaire regarding the practice of neonatal encephalopathy was mailed to clinical leads of registered neonatal intensive care units.
Result: 56.2% of the units were incapable of offering therapeutic hypothermia because of the reasons such as the shortage of human/medical resources (85.1%) and limited number of cases (21.1%). Eighty-nine centres provided therapeutic hypothermia using either selective-head cooling (88.8%) or whole-body cooling (11.2%). Various target temperatures and cooling durations were used; 20.2% of the units cooled infants without using purpose-built equipments, whereas 14.6% did not continuously monitor the body temperature.
Discussion: Only 43.8% of the units provided therapeutic hypothermia. Even in centres where hypothermia was offered, adherence to the standard protocols was extremely poor. To secure the safety and efficacy, further promotion of the standard cooling protocols is required; an efficient cooling centre network has to be established by optimizing the work forth distribution and transportation system.

DOI： 10.1111/j.1651-2227.2011.02562.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

L1CAM molecule is a cell adhesion molecule in nervous and enteric systems and is responsible for X-linked hydrocephalus (XLH) spectrum, which is a rare condition with severe congenital hydrocephalus, dysgenesis of the corpus callosum, intellectual disability, spasticity, and adducted thumbs. Several cases of XLH accompanied by Hirschsprung disease (HSCR) have been reported in the literature, but whether HSCR results from a gain-of-function mutation in cases with XLH, i.e., a neomorphic mutation, or the severe end of the L1CAM mutation spectrum remains unclear. The present patient was a Japanese boy with severe congenital hydrocephalus with aqueductal stenosis as well as hypoplasia of the corpus callosum. HSCR had been confirmed by a biopsy. A mutation analysis of the L1CAM gene showed a C61T mutation in exon 1, resulting in a truncating nonsense mutation at amino acid position 21 and producing an extremely short protein that was unlikely to interact with other proteins. These findings suggest that XLH-HSC Rrepresents the severe end of the XLH spectrum, rather than a neomorphic mutation. A thorough abdominal investigation to rule out HSCR should be considered in patients with XLH accompanied by severe constipation. (C) 2012 Wiley Periodicals, Inc.

DOI： 10.1002/ajmg.a.35245

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Neonatal encephalopathy (NE) secondary to intrapartum asphyxia remains a major cause of post-natal death and permanent neurological deficits worldwide. Supportive therapy has been the mainstay of the treatment until recent series of large clinical trials demonstrating benefit of therapeutic hypothermia (TH) in this high risk population. Now the International Liaison Committee on Resuscitation (ILCOR) recommends TH as a standard of care with the protocols used in the large clinical trials as tentative standard protocols.
Our goal is to develop a nationwide consensus practice guideline not only consistent with the international standard protocols but also practical and compatible with the current medical system in Japan.
In summary, TH should be offered to newborn infants born &gt;= 36 weeks gestational age and birth weight &gt;= 1800 g exhibiting clinical signs of moderate to severe NE as well as evidence of hypoxia-ischemia, i.e. 10 min Apgar score, &lt;= 5, a need for resuscitation at 10 mm, blood pH &lt; 7.00, or base deficit &gt;= 16 mmol/L. TH should be conducted in the NICUs capable of multidisciplinary care and under the standard protocols, i.e. utilization of cooling device, target (rectal or esophageal) temperatures at 33.5 +/- 0.5 and 34.5 +/- 0.5 degrees C for whole body and selective head cooling respectively, duration of TH for 72 h, gradual rewarming not exceeding the rate of 0.5 degrees C/h. Long term follow-up with multidisciplinary approach including standardized psychological assessment is warranted. (C) 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.braindev.2011.06.009

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE INC  

Perinatal brain injury in term infants remains a significant clinical problem. Recently a change appears to have occurred in the pattern of such injuries. We sought to characterize the incidence, etiology, clinical manifestations, and outcomes of these injuries. A retrospective chart review identified clinical characteristics of neuroimaging, electroencephalography, and placental pathologic findings. Perinatal depression was defined as hypotonia and the need for respiratory support. From January 2004-December 2009, 29,597 term deliveries occurred. Brain injuries in 33 infants (live term births) included hypoxic-ischemic encephalopathy (n = 8; 0.27/1000), subdural hemorrhage (n = 10; 0.34/1000), intraventricular/intraparenchymal hemorrhage (n = 5; 0.17/1000), and focal cerebral infarctions (n = 4; 0.14/1000). Thirteen of 33 infants (39%) were triaged to a regular nursery. Delayed presentations included apnea (n = 6), desaturation episodes (n = 3), and seizures (n = 4). Twenty of 33 (61%) were admitted directly to the neonatal intensive care unit because of perinatal depression or evolving hypoxic-ischemic encephalopathy. Clinical signs included seizures (n = 12) and apnea (n = 2). Nine of 19 manifested electroencephalographic seizures. Pathology included chorioamnionitis (n = 7) and fetal thrombotic vasculopathy (n = 5). The latter was associated with focal cerebral infarctions in 3/4 cases. Most cases attributable to perinatal brain injury, except for evolving hypoxic-ischemic encephalopathy, are not identified according to any perinatal characteristics until the onset of signs, limiting opportunities for prevention. (C) 2012 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.pediatrneurol.2011.11.011

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

DOI： 10.1016/j.braindev.2011.06.008

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATL ACAD SCIENCES  

Enhancement of cerebral blood flow by hypoxia is critical for brain function, but signaling systems underlying its regulation have been unclear. We report a pathway mediating hypoxia-induced cerebral vasodilation in studies monitoring vascular disposition in cerebellar slices and in intact mouse brains using two-photon intravital laser scanning microscopy. In this cascade, hypoxia elicits cerebral vasodilation via the coordinate actions of H2S formed by cystathionine beta-synthase (CBS) and CO generated by heme oxygenase (HO)-2. Hypoxia diminishes CO generation by HO-2, an oxygen sensor. The constitutive CO physiologically inhibits CBS, and hypoxia leads to increased levels of H2S that mediate the vasodilation of precapillary arterioles. Mice with targeted deletion of HO-2 or CBS display impaired vascular responses to hypoxia. Thus, in intact adult brain cerebral cortex of HO-2-null mice, imaging mass spectrometry reveals an impaired ability to maintain ATP levels on hypoxia.

DOI： 10.1073/pnas.1119658109

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記述言語：英語   掲載種別：論文集(書籍)内論文   出版者・発行元：Elsevier Inc.  

DOI： 10.1016/B978-1-4377-3611-3.00003-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MOSBY-ELSEVIER  

Objective To determine whether hypothermia modulates acquisition of sleep-wake cycling in term neonates with moderate to severe hypoxic-ischemic encephalopathy (HIE) and the relationship to outcome.
Study design Twenty-nine term infants with moderate to severe HIE treated with selective head cooling were evaluated. All were monitored with amplitude-integrated electroencephalography during and video electroencephalography immediately after hypothermia for &gt;= 72 hours. Electroencephalograpic data were analyzed for background and sleep-wake cycling. Abnormal outcome included death or severe global neurodevelopmental disability &gt;= 18 months.
Results Acquisition of sleep-wake cycling was noted in nine infants by 72 hours, in 13 by 96 hours, 19 by 120 hours, and 22 by 144 hours. Presence of sleep-wake cycling was associated with normal outcome, that is, 14 of 22 (64%), versus abnormal outcome, that is, none of seven without sleep-wake cycling (P = .006). The presence of sleep-wake cycling by 120 hours had a positive predictive value of 68% and negative predictive value of 90%. Magnetic resonance imaging abnormalities were related to onset of sleep-wake cycling.
Conclusions Although onset of sleep-wake cycling is markedly delayed in term neonates with moderate to severe HIE treated with hypothermia, approximately 65% with acquisition of cycling have a normal outcome. Sleep-wake cycling is an important additional tool for assessing recovery in term infants with moderate to severe HIE treated with hypothermia. (J Pediatr 2011; 159: 232-7).

DOI： 10.1016/j.jpeds.2011.01.006

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE INC  

A boy with genetically confirmed Alagille syndrome was incidentally found to manifest striking diffuse hyperintensity of the white matter on T(2)-weighted cranial magnetic resonance images. He never exhibited signs of hepatic encephalopathy. For his progressive liver failure, he underwent a live-donor liver transplant at age 2 years, which unexpectedly resulted in a near-complete resolution of the diffuse white matter lesion. Reversible white matter lesions attributed to cerebral edema were reported in adult patients with liver cirrhosis, but not in the pediatric population. The diffuse reversible white matter lesion in the present case demonstrated T(2) hyperintensity, coupled with restricted diffusion confirmed by apparent diffusion coefficient, and was suggestive of etiologies such as ischemia or cytotoxic edema rather than vasogenic edema. (C) 2011 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.pediatrneurol.2011.02.009

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

BACKGROUND AND IMPORTANCE: Solitary fibrous tumor (SFT) has been previously reported for its wide variety of presentations and atypical sites. We report a case of recurrent SFT with multiple intracranial and spinal lesions.
CLINICAL PRESENTATION: A 45-year-old female with recurrent right frontoparietal SFT was found to have multiple intracranial and spinal lesions. Most of the lesions are asymptomatic. Each of the intracranial and spinal lesions has been confirmed histologically. In 1999 the patient was found to have a single right temporal SFT and had a gross total resection of the lesion. In 2005 the patient underwent a second gross total resection for the recurrence of the right temporal-parietal lesion, followed by radiation therapy. In 2009 she underwent a third and fourth gross total resection of the right frontoparietal lesion, and the L4-5 mass, as well as a cervical laminectomy for an extramedullary spinal lesion causing spinal compression.
CONCLUSION: This is the first case report of recurrent SFT with multiple intracranial and spinal lesions. This case illustrates the nature of recurrence and multiplicity of SFT and raises the importance of a thorough investigation, especially in the entire neuroaxis, in patients with the diagnosis of SFT. This case also questions the justification of the name that was given to this tumor.

DOI： 10.1227/NEU.0b013e31820a1573

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER IRELAND LTD  

Background: Therapeutic hypothermia has been associated with improved outcomes in term infants particularly in those who present with moderate hypoxic-ischemic encephalopathy (HIE). However, in the three major studies the time to initiate cooling was at approximately 4.5 postnatal hours.
Objective: To determine in term infants who meet criteria for therapeutic hypothermia whether specific clinical and/or biochemical parameters might identify those high risk infants destined for abnormal neurodevelopmental outcome even sooner than is currently possible.
Design/methods: Retrospective chart review for the following parameters: gestational age, birth weight, sex, labor complications, mode of delivery, 10 min Apgar &lt;= 3, cardio-pulmonary resuscitation in the delivery room, cord arterial pH and base deficit, initial postnatal pH and base deficit obtained within 1 h, aEEG, Sarnat staging and seizures at enrollment. Abnormal outcome included death and neurodevelopmental deficits.
Results: At a single tertiary care center in a metropolitan area, 45 term infants with moderate to severe HIE were treated with selective head cooling initiated at a mean of 4.69 +/- 0.79 h of life; 43/45(96%) were outborn. Five (11%) infants died and of survivors 26(58%) are normal and 14(31%) infants are abnormal at follow-up ranging from 12 to 26 months. Infants with abnormal vs. normal outcome were of comparable gestational age, birth weight with no differences in any parameters between groups except that in infants with abnormal vs. normal outcome the postnatal pH obtained within the first postnatal hour was lower, i.e. 6.87 +/- 0.15 vs. 7.00 +/- 0.22 (p = 0.02) and abnormal infants were more likely to present with severe encephalopathy, i.e. 15/19(79%) vs. 6/26(23%) (p = 0.0002) and clinical seizures, i.e. 14/19(74%) vs. 10/26 (38%) (p = 0.03) on admission.
Conclusions: High risk infants who become candidates for therapeutic hypothermia and ultimately have an abnormal outcome may be identified by an additional early postnatal biochemical marker, i.e. the presence of profound metabolic acidosis. An earlier induction of hypothermia that currently occurs particularly in infants with severe encephalopathy may potentially improve outcome. Given that most infants are outborn, a time sensitive education metaphor termed Chain of Brain Preservation may facilitate early recognition of high risk infants and thus earlier treatment. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.resuscitation.2010.08.001

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SAGE PUBLICATIONS INC  

A term male newborn was noted to have severe diffuse hypotonia, hyporeflexia, hepatosplenomegaly, and characteristic abnormal facies of Zellweger syndrome, the diagnosis of which was confirmed by identification of 2 mutations including Nt2098insT, a frameshift with premature stop codon in exon 13, as well as a novel second mutation at Nt3038G -&gt; A (Arg1013His) on skin fibroblast testing. His brain magnetic resonance imaging (MRI) demonstrated bilateral germinolytic cysts with unilateral hemorrhagic transformation. Germinolytic cysts are one of the characteristic radiographic features of Zellweger syndrome, but germinal matrix hemorrhage has never been reported. Germinal matrix hemorrhage is common in premature infants, but found in only 4% of normal term infants. Germinal matrix hemorrhage was seen in a case of Zellweger syndrome with a novel mutation.

DOI： 10.1177/0883073810365545

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE INC  

Restricted diffusion within the splenium of the corpus callosum was described in various conditions, but is not a prominent finding in magnetic resonance imaging after neonatal hypoxic-ischemic encephalopathy. Perinatal characteristics were reviewed in 42 term neonates with hypoxic-ischemic encephalopathy treated with selective head cooling. Neonatal images of 34 infants were reviewed. Ten of 34 (29%) infants demonstrated restricted diffusion changes within the splenium of the corpus callosum, with a significantly higher incidence of death or severe developmental delay, compared with infants without changes in the splenium of the corpus callosum (n = 24) (P = 0.002). The positive predictive value of changes in the splenium of the corpus callosum regarding poor outcomes or death was 90%. Changes in the splenium of the corpus callosum were also associated with lower birth weights, larger base deficits in cord arterial gas, and more severe encephalopathy during enrollment in selective head cooling. Restricted diffusion within the splenium of the corpus callosum of term infants with hypoxic-ischemic encephalopathy is often associated with extensive brain injury, and in these circumstances appears to be an early neuroradiologic marker of adverse neurologic outcomes. (C) 2010 by Elsevier Inc. All rights reserved.

DOI： 10.1016/j.pediatrneurol.2010.04.014

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE INC  

A pediatric patient with diagnosis of Parry-Romberg syndrome, or progressive hemifacial atrophy, presented with new-onset unilateral alien hand syndrome, which was attributed to focal progressive atrophy and gliosis in the contralateral thalamus observed on serial neuroimaging. This case illustrates not only the clinical-radiographic correlation between alien hand syndrome and contralateral thalamic lesion, but also involvement of deep gray structure in Parry-Romberg syndrome causing a rare movement disorder. (C) 2010 by Elsevier Inc. All rights reserved.

DOI： 10.1016/j.pediatrneurol.2009.11.010

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL PUBLISHING, INC  

Stimulus-induced seizure is a well-described entity in children and adults and is often associated with severe epilepsy and neurologic impairment. The occurrence and clinical expression of stimulus-induced seizure in three sick neonates is described. The cohort comprised 26 neonates undergoing continuous video-electroencephalography (vEEG) monitoring between July and December 2007. Three cases (11.5%) of stimulus-induced seizure were identified. The underlying injury included stroke (n = 2) and intraventricular hemorrhage (n = 1). Seizures were induced by physical stimuli such as stroking the forehead, movements, (i.e., starting to feed), and one during endotracheal suctioning. Stimulus-evoked electrographic patterns have been reported in neonates with brain injury; however, these events appear to be more common than previously thought, especially with the abundance of subclinical seizures observed in these patients. These observations stress the usefulness of vEEG monitoring and importance of care to avoid unnecessary stimuli in at-risk neonates.

DOI： 10.1111/j.1528-1167.2009.02288.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE INC  

Selective head cooling was used to treat infants at risk of developing encephalopathy within 6 hours as part of a practice plan. Amplitude-integrated electroencephalography and raw, single-channel electroencephalography tracings were performed continuously during cooling. Routine electroencephalography was performed intermittently during, and video electroencephalography immediately after, selective head cooling. Magnetic resonance imaging was performed at the end of week 1. We sought a better delineation of the occurrence and timing of clinical and electrographic seizures during selective head cooling. Twenty term infants are described. Eleven received chest compressions, all at pH &lt;7. Upon admission, encephalopathy was characterized clinically as moderate (n = 13) or severe (n = 7), and by amplitude-integrated electroencephalography as moderate (n = 8), severe (n = 6), or indeterminate (n = 6). Clinical seizures (n = 18) were most prominent on day 1. Amplitude-integrated electroencephalography seizures (n = 9) were evident upon admission and on day 1 (n = 19), and were continuous between 24-36 hours (n = 9). Amplitude-integrated electroencephalography seizures were confirmed by routine electroencephalograpby. Magnetic resonance imaging was abnormal in nine infants, with predominantly bilateral involvement of the basal ganglia (n = 8). Magnesium was at &lt;= 1.2 mg/dL (n = 9). Electrographic seizures were very frequent, and often lacked a clinical correlate. Electroencephalography monitoring during cooling should be considered to detect subclinical seizures. (C) 2009 by Elsevier Inc. All rights reserved.

DOI： 10.1016/j.pediatrneurol.2009.05.004

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担当ページ：664-668  

これまでの新生児医療は, 緻密な呼吸栄養管理などを中心とするsupportive careが中心であった. ここ数年で, 遺伝子治療や核酸医薬品をはじめとする新生児期発症の遺伝性疾患に対して病態に基づいた疾患特異的治療法が保険収載され, 臨床で使用されるようになった. 加えて, 人工知能やコンピュータ処理能力の著しい進歩により全ゲノム解析の期間が短縮された. これにより, 諸外国において重症新生児を対象とした網羅的遺伝子診断の臨床応用が広がりつつある. わが国においては, 小児期以降の未診断患者を対象とした網羅的遺伝子診断研究は行われてきたが, 重症新生児を対象とした迅速な網羅的遺伝子診断の取り組みはこれまでになかった. 筆者らは, 2019年から国内の周産期医療センターと連携し, 新生児集中治療室に入院する重症新生児に対する迅速な遺伝子診断の研究開発を行っている.

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担当ページ：357-360  

「Key Points」
(1)網羅的遺伝子解析に要する解析期間が短縮され, 欧米を中心に, ゲノム診断が小児・新生児集中治療の現場で活用され始めている.
(2)わが国でも重症新生児に対するゲノム診断の研究が行われ, 約半数で診断が確定し, そのうち約半数で診療方針に影響があった.
(3)重症新生児で迅速なゲノム診断が必要と考えられる場合には, 施設長の実施許可があれば, 研究参加できる枠組みが用意されている.
(4)重症新生児に対するゲノム診断が将来的に保険収載されることが期待される.

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担当ページ：51  

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担当ページ：1426-1427, 1551-1552  

【CDC42（関連疾患：武内・小崎症候群）】
「1. 名称・分類・遺伝子座」 CDC42の遺伝子座位は1p36であり, RHOAおよびRAC1とともにスーパーファミリーを形成する低分子量Gタンパク質(small GTPase)である. 「2. 遺伝子の発現・機能」 Gタンパク質は2つに大別され, 1つは, 単量体で機能する低分子量Gタンパク質(small GTPase)であり, もう1つは, α, β, γのサブユニットからなるヘテロ三量体Gタンパク質である. CDC42の属する前者の低分子量Gタンパク質は, GTP結合タンパクであり, 結合している2種類のグアニンヌクレオチド(GTPあるいはGDP)の立体構造の違いにより, エフェクターへの結合能が変化し, 下流のシグナル伝達を制御する.

【NPC1 （ Niemann-Pick病C型）】
「1. 名称・分類, 遺伝子座」 NPC1の遺伝子座位は18q11.2であり, NPC2の遺伝子座位は14q24.3である. 「2. 遺伝子の構造・産物・発見の経緯」 NPC1は, 24のエクソンからなる遺伝子である. NPC1タンパクは, 1,278個のアミノ酸からなる13回膜貫通型膜タンパクであり, N末端のNPC領域はコレステロール結合能をもつ. 「3. 遺伝子の発現・機能」 コレステロールは, 通常, 細胞膜にあるLDL受容体を介して細胞内へ取り込まれる. ライソゾーム内に取り込まれたコレステロールエステルは, 酸性リパーゼにより遊離コレステロールとなる.

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担当ページ：86  

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担当ページ：1075-1081  

Summary
●人類は, これまで医学研究を通じて, エビデンスを積み上げることで医療を発展させてきた.
●研究活動のルールと診療活動のルールの違いや研究倫理についての理解が重要である.
●小児科学の社会医学の側面に加えて, 分子生物学, 再生医学, データサイエンス等の進歩により, 小児科学の研究対象は広がっている.

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総ページ数：70   担当ページ：589-594   記述言語：日本語 著書種別：学術書

網羅的遺伝子解析技術の飛躍的な進歩により, 臨床所見のみからは診断が困難であった希少疾患の確定診断や, 新規疾患の発見・確立が可能となった. "武内・小崎症候群(OMIM #616737)" は, 日本医療研究開発機構(AMED)の難病克服プロジェクトのひとつであるIRUD(未診断疾患イニシアチブ)を通じて, わが国より提唱, 確立されたヒト疾患である. 本疾患は知的障害, 巨大血小板性血小板減少症, リンパ浮腫, 感音性難聴, 脳構造異常, 免疫不全と易感染性, 甲状腺機能低下などを呈し, CDC42遺伝子にヘテロ接合性のアミノ酸置換変異(p.Tyr64Cysなど)を有することを特徴とする. 関連学会を中心に診断基準が作成され, 2019年7月から厚生労働省小児慢性特定疾病に収載されている. 国内外で複数の本疾患患者が同定されているが, 本疾患に対する治療法はいまだ存在せず, 疾患特異的治療法の開発が強く望まれている. IRUDをさらに発展させたIRUD-Beyondの一環として, 武内・小崎症候群に対する特異的治療法をドラッグリポジショニングにより開発することをめざす "CDC42阻害剤による武内・小崎症候群の治療法の開発研究班" が組織され, 活動を開始した. 細胞などを用いたin vitro実験系と疾患モデル動物などのin vivo系を組み合わせた研究により, 既承認薬のドラッグリポジショニングを効率的に推進し, 非臨床POC(proof of concept)を獲得することを目標としている.

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担当ページ：654-656  

新生児期の痙攣性発作(seizure)は, 乳幼児期のそれとは大きく異なり, 明らかな身体症状を伴わず脳波上でのみ痙攣が確認されるなど, 見た目からだけでは非痙攣性の発作や動作と鑑別が困難な場面にしばしば遭遇する. 新生児痙攣は, 急性の脳障害, 神経疾患の徴候であることが多く, 注意を要する. 痙攣の診断が遅れたり, コントロールが不良な場合は, 神経学的予後に悪影響を及ぼすことがあるので, 非痙攣性発作と痙攣性発作を鑑別し, 必要な場合には迅速に治療を行う. 「新生児発作」 新生児の発作(spell)は, いわゆる真の痙攣である痙攣性発作(seizure)と非痙攣性発作に分類することができる.

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担当ページ：1123-1127  

「重症の小児・新生児に対する網羅的遺伝子診断の課題と海外における検討」ヒトゲノム全塩基配列の解析を目指して1990年に始まったヒトゲノム計画は, サンガー法を用いて13年の歳月と30億ドル以上の資金を費やして行われた. 30年経った現在, 全ゲノム解析技術は加速度的に発展し, わずか数日間, 1000ドル程度の費用で全ゲノム解析が行えるようになった. 同時に, 遺伝子の分子機構の解明研究も飛躍的に進展し, 集中治療室への入室を要するような重症小児・新生児の診療に対する網羅的遺伝子解析の臨床応用が期待されている. ところが, 従来の網羅的遺伝子診断法は診断までに平均で半年以上の時間を要するため, 病状が時々刻々と変化する集中治療の医療現場で活用することは容易ではなかった. 2000年半ばに登場した次世代シーケンサーにより, 塩基配列の解読速度は大幅に短縮された.

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総ページ数：xxi, 631p   記述言語：日本語

CiNii Books

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総ページ数：365   担当ページ：121   記述言語：日本語

CiNii Books

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担当ページ：52-57  

武内・小崎症候群〔Takenouchi-Kosaki Syndrome（OMIM #616737）〕は，知的障害と巨大血小板性血小板減少症を特徴とし，CDC42 遺伝子の特定の新生突然変異に起因する稀な先天異常症候群である。本疾患は，日本医療研究開発機構（AMED）によって2015年から行われている「未診断疾患イニシアチブ（IRUD）」を通じて，似た症状を呈する複数の患者の研究協力により，新規ヒト疾患として発見・確立された。本疾患は，巨大血小板性血小板減少症，知的障害に加えて，脳構造異常，特徴的顔貌，感音性難聴，屈指，免疫不全による反復感染症，甲状腺機能低下症などの多彩な症状を呈することが特徴である。本疾患の病態については，まだ未解明な点が多く，今後の研究による病態解明が待たれるところである。血小板減少を伴う知的障害患者では，本疾患を鑑別に入れ，末梢血塗抹標本検査で，巨大血小板の有無を確認することが重要である。

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担当ページ：1763-1771   記述言語：日本語

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担当ページ：1725-1732   記述言語：日本語

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担当ページ：5-18  

-2017年10月25日 KKRホテル東京にて- <司会(五十嵐)> 雑誌『小児内科』は, このたび創刊50周年を迎えました. これを記念して, わが国の小児のおかれている現状と, 今後生じる小児の医療・保健の課題に対してどのような取り組みが必要かについて伺うために, 臨床・研究の現場で現在ご活躍中の中堅小児科医の先生方にお集まりいただきました. 小児科医のこれからの方向性についてご意見をいただければ幸いです. 「第1章 子どもたちのために」 ちょっとおせっかいかもしれないけれど -子育て支援と貧困について <司会> わが国は, すでに人口減少化の大きな流れのなかに入っています. 平成28年の合計特殊出生率は1.44, 出生数も98万人に減少し, 地方では過疎化が進んでいます. 子どもの育ちを総合的に評価するThe Child Development Indexで, わが国は世界一の地位を占めています.

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担当ページ：811-815  

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担当ページ：1003-1005  

先天異常症候群では, 遺伝性または非遺伝性の多様な疾患が含まれ, 診断困難な場合が多い. 今回, 出生時に先天異常を認めたが診断がつかず, 14歳時に臨床的にCHARGE症候群と診断したものの, 次世代シーケンス法による網羅的遺伝子解析により Mowat-Wilson 症候群の確定診断となった14歳男子例を経験したので報告する. 「症例」症例 14歳, 男子. 主訴 発熱, 咳嗽. 家族歴 特記すべき事項なし. 出生歴・既往歴 妊娠38週6日, 2,890g, 自然分娩にて出生. 出生時に耳介低位, 耳介奇形, 停留精巣, 前置陰嚢, 尿道下裂, 口蓋垂裂を認めた. 染色体検査(G-分染法)は46,XYで異常を認めなかった. 腹部MRI検査にて腹腔内に精巣を認め, 前立腺は正常であった. 眼底検査および細隙灯顕微鏡検査では異常を認めなかった.

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担当ページ：128-133  

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総ページ数：231p   記述言語：日本語

CiNii Books

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担当ページ：519-520  

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担当ページ：708-709  

脳の形態異常は, 顕微鏡的な形態異常から肉眼的な形態異常まで非常に多岐にわたる. 中枢神経系の中核をなす脳は, 神経幹細胞からの神経細胞の産生, 神経細胞の遊走, グリア細胞の形成, シナプス形成, ミエリン形成といった過程を経て形成される. このような脳の発生段階のいずれかに異常が生じた場合, その段階によってさまざまな形態異常を生じる. 脳の形態異常の原因には, 遺伝子異常などの内的要因だけでなく, 感染症や出血, 薬物曝露といった環境要因も含まれる. 以下に, 代表的な中枢神経系の形態異常について述べる. 「各論」 [1. 孔脳症 (porencephaly) ] 大脳半球に嚢疱または空洞がみられる脳形成異常であり, 脳性麻痺, 特に片麻痺の原因となる. このほかにも, てんかん, 精神運動発達遅滞を呈することがある. 胎生期における脳梗塞などの脳血管障害の結果として発生すると推測されているが, 多くの場合原因は不明である.

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担当ページ：328-333  

出生前後の低酸素や虚血によって中等度以上の脳症を発症した新生児にとって, 低体温療法は臨床エビデンスに支持される唯一の脳保護療法である. 一方で低体温療法の治療効果は, 6～9名を治療してようやく1名の予後を改善できるレベルにとどまる. 十分な効果を死守するために, 国内外の蘇生療法ガイドラインでは, 大規模ランダム化臨床研究(以下, 便宜上RCTと記載)で用いられた導入基準と方法を厳格に順守するように求めている. 本稿ではConsensus 2010による新生児低体温療法の推奨以降, 日本の新生児医療従事者が一丸となってエビデンスへの回帰を成し遂げた過程を簡単に振り返るとともに, 今後日本の臨床家がどのような戦略で低体温療法の効果を増大し, 世界へのエビデンス発信を進めるのかを, Baby cooling Japan登録症例の分析結果の考察を交えて議論する.

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総ページ数：冊   記述言語：日本語

CiNii Books

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担当ページ：1167-1173  

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総ページ数：xvi, 887p   記述言語：日本語

CiNii Books

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担当ページ：240-241  

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担当ページ：906-909  

「Q1 低酸素状態に陥った新生児の脳を冷やすことで, どのような脳保護メカニズムが働くのですか? 分かりやすく教えてください.」 低酸素性虚血性脳症とは, 胎盤血流の遮断を端緒として低酸素虚血に陥った神経細胞で有害な連鎖化学反応が起こり, 神経細胞が障害される現象である. 低体温療法は, 脳全体のエネルギー消費を抑え, これらの有害な化学反応を多段階で阻害することにより, 脳保護に働く. 「1. 低酸素性虚血に陥ると, 神経細胞はどのように障害されるか」低酸素性虚血性障害の強い神経細胞は壊死に陥る. 壊死を免れた神経細胞では, 再酸素化と再還流により, エネルギー代謝が一時的に回復する. しかし, 分子レベルでは有害な化学反応が進行しており, 一定の潜伏期間を経た後, 徐々にアポトーシス（神経細胞死）が起こり, 神経細胞が脱落する. 図1に示すように, 低酸素性虚血が起こると, ATP低下, 興奮性アミノ酸の放出, 低酸素性脱分極によるカルシウムイオンの細胞内流入など分子レベルの反応が次々と生じ, 最終的には一酸化窒素や活性酸素が産生される）.

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総ページ数：xiv, 350 p.   担当ページ：27-45   記述言語：英語

CiNii Books

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記述言語：英語

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担当ページ：1697-1702  

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記述言語：日本語

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担当ページ：781-784  

「これがエビデンスだ！」[現在のところ低体温療法だけが唯一, ヒトの新生児低酸素性虚血性脳症の予後を有意に改善することが科学的に証明されている治療法である. ] 欧米を中心に新生児低体温療法が広く行われるようになっているという世界的な流れを受けて, 新生児蘇生法の中でも標準治療として推奨された. 新生児低酸素性虚血性脳症は, 死亡または重篤な神経学的後遺症を残すことが多く, 最も重要な周産期疾患の一つである. 患児だけでなく, 家族そして社会全体の長期にわたる負担も大きな問題であり, 治療法が渇望されていた. しかしながら, 低酸素や虚血といった病態は根本的治療が難しく, これまで予後を改善させる治療法が存在しなかった. 近年, 動物実験から低体温療法の有効性が確認され, さらに複数の大規模臨床治験においてヒトでも比較的安全に有意に予後を改善することが示された. これを受けて, すでに欧米では低体温療法が広く行われるようになっている.

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総ページ数：150p   記述言語：日本語

CiNii Books

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総ページ数：143p   記述言語：日本語

CiNii Books

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担当ページ：1428-1433   記述言語：日本語

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総ページ数：170   記述言語：日本語

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担当ページ：1260-1264   記述言語：日本語 著書種別：学術書

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記述言語：日本語   出版者・発行元：(一社)日本周産期・新生児医学会  

先天性Glycosylphosphatidylinositol(GPI)欠損症は,様々なタンパク質を細胞膜に繋ぎとめるGPIアンカーの合成等に関係する遺伝子の変異により発症する疾患であり,知的障害,運動発達遅滞,てんかん等を示す.国内で患者数は約50人と稀な疾患であり,家族歴がない場合は診断に難渋する.主症状として知的障害・運動発達障害等が挙げられているが,周産期異常を伴わないとされる.今回重症新生児仮死としてNICUへ搬送され,その後も傾眠傾向,筋緊張低下,嚥下障害等の症状が持続し,出生時より症状を示したと考えられる先天性GPI欠損症の一例を経験したため報告する.(著者抄録)

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J04116&link_issn=&doc_id=20240913470025&doc_link_id=10.34456%2Fjjspnm.60.2_330&url=https%3A%2F%2Fdoi.org%2F10.34456%2Fjjspnm.60.2_330&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

記述言語：日本語   出版者・発行元：(一社)日本てんかん学会  

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語   出版者・発行元：日本小児呼吸器学会  

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記述言語：日本語   出版者・発行元：日本小児呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本周産期・新生児医学会  

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記述言語：日本語   出版者・発行元：(一社)日本周産期・新生児医学会  

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記述言語：日本語   出版者・発行元：(一社)日本周産期・新生児医学会  

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記述言語：日本語   出版者・発行元：(一社)日本周産期・新生児医学会  

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記述言語：日本語   出版者・発行元：(一社)日本周産期・新生児医学会  

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記述言語：日本語   出版者・発行元：(一社)日本周産期・新生児医学会  

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記述言語：日本語   出版者・発行元：(一社)日本周産期・新生児医学会  

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記述言語：日本語   出版者・発行元：(一社)日本周産期・新生児医学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

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記述言語：日本語   出版者・発行元：(株)診断と治療社  

＜文献概要＞▼武内・小崎症候群は,巨大血小板性血小板低下症(血小板が大きく,血小板数が少ないこと)を特徴とし,CDC42遺伝子のヘテロ接合性機能亢進型変異によって発症する多系統疾患である.▼免疫性血小板減少症(ITP)との鑑別の観点からは,本疾患患者では,末梢血に巨大血小板性血小板低下がみとめられるほかに,知的障害,特徴的顔貌,感音難聴,屈指など多彩な全身性の症状を呈することがポイントである.▼CDC42阻害薬による治療研究がすすめられている.

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記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語   出版者・発行元：(一社)日本周産期・新生児医学会  

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J04116&link_issn=&doc_id=20240515600004&doc_link_id=10.34456%2Fjjspnm.59.4_447&url=https%3A%2F%2Fdoi.org%2F10.34456%2Fjjspnm.59.4_447&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

ADNP(activity-dependent neuroprotective protein)症候群は自閉スペクトラム症,知的発達症,特徴的な顔貌を呈し,乳歯の早期萠出を特徴とする.症例は13歳男子,全エクソーム解析でNM_001282531.2(ADNP):c.2496_2499delが同定され,同変異の既報より知的発達症は重度であった.今後,症例が集積され遺伝型・表現型相関の解明が期待される.(著者抄録)

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J01232&link_issn=&doc_id=20240305170008&doc_link_id=%2Fcl1nohat%2F2024%2F005602%2F012%2F0142-0144%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcl1nohat%2F2024%2F005602%2F012%2F0142-0144%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語   出版者・発行元：日本レックリングハウゼン病学会  

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記述言語：日本語   出版者・発行元：(公社)日本新生児成育医学会  

Floating-Harbor症候群はSRCAP遺伝子の突然変異により発症する常染色体顕性遺伝の疾患である。全世界で約100例程度の報告しかない非常にまれな疾患であり,低身長,言語発達遅滞,特異的顔貌を特徴とする。今回早産,低出生体重児で出生し,骨関節内の点状石灰化を認めたFloating-Harbor症候群の乳児例を経験した。出生時より特異的顔貌,両側の第1指趾の短縮を認め,単純X線写真にて,足関節内の点状石灰化病変を認めた。上咽頭の狭窄・気管軟化症の併存もあり点状軟骨異形成症が疑われたが,全エクソーム解析にてSRCAP遺伝子にde novoのフレームシフトバリアントが同定されFloating-Harbor症候群と診断された。本症例は人工呼吸器離脱困難のため気管切開術が施行されており,既知のFloating-Harbor症候群の報告と比較し重症である。Floating-Harbor症候群の表現型スペクトラムはこれまでの報告より広い可能性が示唆された。(著者抄録)

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語   出版者・発行元：(株)東京医学社  

＜文献概要＞はじめに 産科医療補償制度は,2009年1月にわが国で世界に先駆けて創設された医療分野における初の無過失補償制度である。本制度の補償金の支払い対象と認定されるためには,本制度における「脳性麻痺」の定義に合致し,一般審査もしくは個別審査における「補償対象基準」を満たし,「除外基準」に該当せず,身体障害者障害程度等級一～二級に相当する「重症度の基準」を満たす必要がある。本稿では,本制度の柱である「脳性麻痺の定義」および「補償対象基準」「除外基準」「重症度の基準」の3つの基準について解説する。

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J00621&link_issn=&doc_id=20240221080007&doc_link_id=10.24479%2Fperi.0000001397&url=https%3A%2F%2Fdoi.org%2F10.24479%2Fperi.0000001397&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

記述言語：日本語   出版者・発行元：(株)東京医学社  

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J00648&link_issn=&doc_id=20231220220026&doc_link_id=10.24479%2Fpm.0000001436&url=https%3A%2F%2Fdoi.org%2F10.24479%2Fpm.0000001436&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

記述言語：日本語   出版者・発行元：(株)メディカ出版  

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J07193&link_issn=&doc_id=20231115020013&doc_link_id=issn%3D2434-4540%26volume%3D36%26issue%3D6%26spage%3D867&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D2434-4540%26volume%3D36%26issue%3D6%26spage%3D867&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語   出版者・発行元：(株)東京医学社  

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J00621&link_issn=&doc_id=20240215030161&doc_link_id=10.24479%2Fperi.0000001381&url=https%3A%2F%2Fdoi.org%2F10.24479%2Fperi.0000001381&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

皮膚および神経に症状を呈する母斑症(神経皮膚症候群)は,皮膚科医と小児科医がともに診療に関わる機会が多い.母斑症は,生殖細胞系列の遺伝子変異にセカンドヒットが加わって発症する疾患群と,体細胞変異のみによって発症する疾患群とに大別される.分子遺伝学的な病態解明と分子標的薬の進歩により,母斑症の治療可能性が増えてきている.診療面では,長期的に多岐にわたる症状に対応するため複数科連携が必須となる.(著者抄録)

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語   出版者・発行元：金原出版(株)  

＜文献概要＞神経線維腫症1型は,小児科診療で遭遇する機会の多い母斑症(神経皮膚症候群)である.NF1遺伝子のヘテロ接合性変異によって発症する遺伝性疾患である.出生後から年齢依存性に症状が増えていくことが特徴である.一般に,幼少期に皮膚のカフェオレ斑が多発することで気づかれることが多いが,成長とともに,神経線維腫とよばれる良性腫瘍が生じる.その他に,骨病変,虹彩や視神経,脳にも過誤腫を認めることがある.成人期以降には,悪性末梢神経鞘腫瘍やその他の悪性腫瘍の発生に注意が必要である.2022年からわが国でも,本疾患に伴うびまん性神経線維腫に対して,セルメチニブ(商品名:コセルゴ)が保険収載された.本薬剤により腫瘍容積を2割程度縮小できる.これまで,本疾患の治療は外科的切除のみであったが,分子標的薬による内科的治療に外科的治療を組み合わせる新しい時代に入ったといえる.

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記述言語：英語   出版者・発行元：(一社)日本血液学会  

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記述言語：日本語   出版者・発行元：(株)医学書院  

＜文献概要＞はじめに 重症新生児のうちの5～10%は,遺伝子異常による疾患を持つとされる.次世代シーケンサーの登場により網羅的遺伝子解析技術が進歩し,DNAのレベルでゲノムを分析することが可能になった.これにより,多くの疾患の原因が明らかになってきている.遺伝学的検査を行う際には,各解析技術の長所および短所をよく理解することに加えて,適切な遺伝カウンセリングを行うことが重要である.本稿では,代表的な遺伝学的検査として,染色体Gバンド検査,マイクロアレイ染色体検査,次世代シーケンサーによる解析について概説し,小児・新生児医療現場への応用について述べる.

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記述言語：日本語   出版者・発行元：(一社)日本周産期・新生児医学会  

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J04116&link_issn=&doc_id=20230919450001&doc_link_id=10.34456%2Fjjspnm.59.2_156&url=https%3A%2F%2Fdoi.org%2F10.34456%2Fjjspnm.59.2_156&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本周産期・新生児医学会  

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記述言語：日本語   出版者・発行元：(一社)日本周産期・新生児医学会  

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記述言語：日本語   出版者・発行元：(一社)日本周産期・新生児医学会  

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記述言語：日本語   出版者・発行元：(一社)日本周産期・新生児医学会  

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記述言語：日本語   出版者・発行元：(一社)日本周産期・新生児医学会  

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記述言語：日本語   出版者・発行元：(一社)日本周産期・新生児医学会  

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記述言語：日本語   出版者・発行元：(一社)日本遺伝カウンセリング学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：英語   出版者・発行元：(一社)日本小児神経学会  

Levetiracetam(LEV)は催奇形性や遺伝子変異原性が比較的少ないとされ,挙児希望のあるてんかん女性でしばしば第一選択薬となる.LEVの高い母乳移行率については広く知られているが,新生児薬物離脱症候群(Neonatal abstinence syndrome;NAS)のリスクに関しては,未だ不明な点が多い.我々は,LEV内服母体から出生し,NASを呈したと考えられる新生児を2例経験した.2例とも妊娠中の胎児発育や心拍モニタリングでは異常を認めず,仮死はなかった.しかし,生後1時間以降,NASスコアはそれぞれ最高4点(傾眠,多呼吸,哺乳力低下),8点(傾眠,筋緊張低下,無呼吸発作,多呼吸)を示し,気管挿管を含む集中管理を要した.比較的安全とされる薬剤についても,妊娠中の胎児への薬物移行は避けられず,新生児の管理には慎重を期す必要がある.妊娠経過や仮死の有無に関わらず,薬剤内服母体から出生した児ではNAS発症のリスクを考慮し,十分な蘇生準備と哺乳が安定するまでの適切な管理が重要である.(著者抄録)

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J01232&link_issn=&doc_id=20221227210008&doc_link_id=%2Fcl1nohat%2F2023%2F005501%2F011%2F0043-0047%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcl1nohat%2F2023%2F005501%2F011%2F0043-0047%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語   出版者・発行元：(一社)日本てんかん学会  

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記述言語：日本語   出版者・発行元：医歯薬出版(株)  

新生児集中治療室に入室する重症新生児・乳児の約1割が遺伝的背景を持つとされる。これらの患者に対して、迅速なゲノム診断を行い、診断結果を診療にいかす取り組みが世界各国で進んでいる。わが国でも、重症新生児・乳児に対して全ゲノム解析研究が行われ、約半数で分子遺伝学的診断が確定し、その半数で診療方針に影響があった。2021年に改定された倫理指針に基づき、研究協力機関として迅速に研究参加でき、遠隔カンファレンスシステムを活用することによって、患者家族に研究内容や結果を説明する遺伝カウンセリングが提供される仕組み作りがはじまっている。迅速な網羅的遺伝子解析はその診断率および非侵襲性から、今後、新生児・小児の急性期医療や集中治療において不可欠な診断技術になると考えられる。わが国のどこで生まれた重症新生児・小児であっても、必要な場合に迅速なゲノム診断と適切な遺伝カウンセリングが受けられる体制の構築が求められている。(著者抄録)

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J00060&link_issn=&doc_id=20220802010010&doc_link_id=issn%3D0039-2359%26volume%3D282%26issue%3D5%26spage%3D385&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0039-2359%26volume%3D282%26issue%3D5%26spage%3D385&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

記述言語：日本語   出版者・発行元：(一社)日本遺伝カウンセリング学会  

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記述言語：日本語   出版者・発行元：(株)東京医学社  

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J00621&link_issn=&doc_id=20220603140007&doc_link_id=10.24479%2Fperi.0000000157&url=https%3A%2F%2Fdoi.org%2F10.24479%2Fperi.0000000157&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

頭の形の精査目的に当院を紹介受診した患者289例の紹介理由と頭蓋骨縫合早期癒合症(CS)有病率について調査した。その結果、患者の平均月齢は23.3±19.7ヵ月で、うちCSと診断されたのは89例(30%)であった。紹介理由は「頭蓋変形」が最多で182例であり、次いで「頭囲が小さい・大きい」「診断済み」「大泉門が狭い・早期に閉鎖」「発達の遅れ」の順であった。今回の調査では、いずれの紹介理由であっても、一定の割合でCSの患者が発見されたことから、些細なことでも専門施設への紹介が望ましいことが示唆された。一方、CSに対する知識はまだ不足しており、発見に至っていない症例もあることが考えられたことから、引き続き情報発信の必要性が示唆された。

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語   出版者・発行元：日本レックリングハウゼン病学会  

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記述言語：日本語   出版者・発行元：日本レックリングハウゼン病学会  

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：(株)東京医学社  

＜Key Points＞(1)網羅的遺伝子解析に要する解析期間が短縮され、欧米を中心に、ゲノム診断が小児・新生児集中治療の現場で活用され始めている。(2)わが国でも重症新生児に対するゲノム診断の研究が行われ、約半数で診断が確定し、そのうち約半数で診療方針に影響があった。(3)重症新生児で迅速なゲノム診断が必要と考えられる場合には、施設長の実施許可があれば、研究参加できる枠組みが用意されている。(4)重症新生児に対するゲノム診断が将来的に保険収載されることが期待される。(著者抄録)

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J00648&link_issn=&doc_id=20220309070021&doc_link_id=10.24479%2Fpm.0000000072&url=https%3A%2F%2Fdoi.org%2F10.24479%2Fpm.0000000072&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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