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Myelin oligodendrocyte glycoprotein antibody-associated disease is a central inflammatory demyelinating disorder that cause diverse neurological symptoms. Paraneoplastic neurologic syndromes occur in association with malignant neoplasms and manifest with a wide range of neuropsychiatric symptoms. Paraneoplastic neurological syndrome is rare in myelin oligodendrocyte glycoprotein antibody-associated disease and, when reported, is typically seen in adults. Herein, we report a 3-year-old girl who presented with lower limb paralysis, urinary retention, and seropositivity for myelin oligodendrocyte glycoprotein antibody. Her symptoms did not respond to various immunotherapies. She was incidentally found to have a cartilaginous choristoma in the neck, after surgical resection of which, she showed symptomatic recovery without recurrence. Immunohistochemical analysis of the resected tumor revealed expression of myelin oligodendrocyte glycoprotein within the cartilage tissue. Based on this case experience, children presenting with myelin oligodendrocyte glycoprotein antibody-associated disease who fail to respond to immunotherapies may need prompt screening for occult tumors.

DOI： 10.1016/j.jneuroim.2025.578674

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In treatable neurometabolic disorders, early diagnosis and prompt initiation of treatment are key to improved survival and outcomes. Biallelic variants in SLC5A6 cause sodium-dependent multivitamin transporter deficiency (OMIM # 618973), which is treatable with high-dose pantothenic acid, biotin, and alpha lipoic acid. So far, the onset has been postnatal in all reported patients. A review of the prenatal imaging showed ventriculomegaly at 32 weeks of gestation. After birth, the infant exhibited developmental regression. At 6 months of age, he developed acute metabolic shock in the setting of a urinary tract infection. Rapid exome analysis identified compound heterozygous pathogenic variants in SLC5A6 and confirmed the diagnosis of sodium-dependent multivitamin transporter deficiency. After the infant was initiated on treatment with high-dose biotin and pantothenic acid, we noted dramatic improvements in the hematological, cutaneous, cardiac, and gastrointestinal symptoms. Although the infant showed no further regression, he continued to have significant psychomotor disability. A review of the findings during pregnancy showed that the infant already had enlarged ventricles in late pregnancy, and neuroimaging on day 12 of birth showed signs of energy failure in late pregnancy. Our review of previously reported patients suggested no clear genotype-phenotype correlations, but there was little intrafamilial variability in disease onset. The present observation, for the first time, provides clinical evidence of a fetal onset in sodium-dependent multivitamin transporter deficiency. The high risk of recurrence and the low intrafamilial variability in disease onset suggest that identification and prenatal treatment in the high-risk group may be of significance.

DOI： 10.1002/ajmg.a.64102

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BACKGROUND: 5 years have passed since the formation of the multidisciplinary consortium 'Knowing & Treating Kosaki and Penttinen Syndromes', two ultra-rare degenerative multisystem syndromes caused by heterozygous activating variants in PDGFRB. Neurological, orthopaedic and vascular deterioration can occur. Case reports of patients treated with tyrosine kinase inhibitors (TKIs) suggest that these drugs may be a therapeutic option in the future. The bi-annual remote meetings provide an opportunity to share knowledge on these syndromes. MATERIAL AND METHODS: The consortium has validated the communication process, standardised follow-up guidelines, established a database to improve the natural history of these syndromes and evaluated the real-world safety and efficacy profile of TKIs by comparing treated and untreated patients. The regulatory framework is in place. RESULTS: As of November 2024, 18 teams in 13 countries have joined the consortium. More than 25 patients have been identified worldwide, either published or unpublished; 7 of them were treated with a TKI. The guidelines include retrospective and prospective sections for each organ affected by the disease and are based on literature and expert opinion. They also include recommendations to standardise the assessment of the efficacy and safety of treatments prescribed under compassionate use. CONCLUSION: The consortium welcomes new teams on an ongoing basis. Recommendations are especially useful in such ultra-rare degenerative diseases. The real-life observational study seems to be an appropriate model to improve knowledge, including the assessment of treatment efficacy when the prevalence of the disease does not allow the setting up of clinical trials.

DOI： 10.1136/jmg-2024-110600

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Tricho-hepato-enteric syndrome (THES), a rare autosomal recessive disorder caused by variants in the SKIC3 or SKIC2 gene, is characterized by intractable diarrhea, woolly hair, growth restriction and liver disease. Here we report a neonatal case of THES with neonatal hemochromatosis, in which the novel compound heterozygous SKIC3 variants NM_014639.4:c.815_816del p.(Gly272AlafsTer9) and NM_014639.4:c.2284G>A p.(Gly762Arg) were identified. Further research is needed to elucidate the mechanisms underlying iron metabolism dysregulation in THES.

DOI： 10.1038/s41439-025-00318-y

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DOI： 10.1002/ajmg.a.64030

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Recurrent somatic mosaic pathogenic variants of RHOA have been observed in a newly identified neuroectodermal syndrome, Ectodermal Dysplasia with Facial Dysmorphism and Acral, Ocular, and Brain Anomalies, Somatic Mosaic [EDFAOB]. All 12 previously reported patients had somatic mosaicism for RHOA variants. Conversely, no patients with non-mosaic germline variants of RHOA have been reported. The absence of non-mosaic patients has been explained by the presumed lethal effect of all RHOA variants in non-mosaic status. Here we report an 11-month-old female with EDFAOB-like features but without Blaschko's skin lesions or asymmetry. Characteristic features included hypertelorism, 2-3 toes cutaneous syndactyly, cleft palate and duplicated uterus and kidney malformations. She carried the non-mosaic de novo germline variant RHOA:c.202C>A,p.(Arg68Ser) near the hotspot in the switch II region in peripheral blood and buccal swabs. The documentation of a living patient with a non-mosaic germline variant of RHOA negates the previous notion that patients with RHOA variants are not viable. The differential diagnosis of a "non-mosaic" RHOA-related disorder would include Ectodermal Dysplasia-Ectrodactyly-Clefting syndrome, as both conditions share ectodermal dysplasia, finger anomalies, and clefting. This phenotypic similarity may be explained by the known molecular interaction between TP63, the gene responsible for EEC syndrome, and RHOA. RHOA is a member of the RAC subfamily of small Rho family guanosine triphosphatases, which include RHOA, RAC1, RAC3, and CDC42 (Takenouchi-Kosaki syndrome). The documentation of germline RHOA-associated intellectual disability in the present article establishes that variants in all three genes of the RAC subfamily of small Rho family GTPases are associated with neurodevelopmental disorders.

DOI： 10.1016/j.ejmg.2025.105019

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Beckwith-Wiedemann spectrum (BWSp) is a genomic imprinting disorder characterized by a wide range of clinical features. Here we report an infant with BWSp and atypical features, for whom long-read sequencing confirmed a de novo CDKN1C variant that occurred on the maternally inherited allele and excluded other genetic etiologies. These findings not only expand the BWSp concept but also highlight the potential value of allelic origin analysis in cases with atypical presentations.

DOI： 10.1038/s41439-025-00316-0

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DOI： 10.1097/MCD.0000000000000514

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INTRODUCTION: Genotype-phenotype correlations in PURA-related neurodevelopmental disorders (PURA-NDDs) remain unclear. This systematic review aimed to clarify these correlations. METHODS: Searches of PubMed and Embase were conducted on 8 August 2024 to identify studies that had investigated genetically diagnosed PURA-NDDs (5q31.3 deletion syndrome and PURA syndrome). All types and languages of studies were included. Study quality was assessed using a 20-item criterion checklist. Genetic and clinical data were extracted from each article and genotype-phenotype correlations were explored. RESULTS: Our analysis included 46 studies encompassing 230 patients with PURA-NDDs (5q31.3 deletion syndrome 18 (8%) and PURA syndrome 212 (92%)). Patients with 5q31.3 deletion syndrome exhibited more congenital defects (50% vs 12%, p<0.0001), respiratory difficulties (94% vs 63%, p=0.013) and walking disability (94% vs 55%, p=0.0026) than patients with PURA syndrome. In PURA syndrome, protein-truncating (nonsense or frameshift) variants were associated with more speech deficits (93% vs 80%, p=0.014) than non-protein-truncating (missense or in-frame) variants. PURA variant location had no effect on congenital defect occurrence or neurodevelopmental outcome. Overall, respiratory difficulties, walking disability and speech deficits were more commonly observed in the following order: 5q31.3 deletion (94%, 94% and 100%, respectively), multiple PUR-repeat deletions (68%, 60% and 95%, respectively), single PUR-repeat deletion or alteration (61%, 53% and 85%, respectively), and deletion or alteration located outside PUR repeats (38%, 33% and 43%, respectively). CONCLUSION: The clinical severity of PURA-NDDs appears to be associated with the deletion/alteration size including PUR repeats rather than the location of PURA variants.

DOI： 10.1136/jmg-2024-110379

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Congenital Heart Defect and Ectodermal Dysplasia (CHDED) is an autosomal dominant disorder caused by the PRKD1 gene. CHDED is characterized by heart defects and ectodermal dysplasia. To date, eight patients with CHDED have been described. Calcifications were present in three patients with CHDED. (two patients; renal calcifications, one patient; brain calcifications). The organ distribution of calcifications in CHDED has been unclear. We report here another patient with CHDED and brain calcifications. The patient was a 9-month-old Japanese girl. She presented with heart defects and ectodermal dysplasia. At 6 months of age, she had generalized seizures, and a CT scan revealed calcifications in the bilateral deep cerebral white matter. The seizures resolved with the administration of levetiracetam. The patient had a de novo, heterozygous pathogenic variant, c.1808G > A, p.(Arg603His), in the PRKD1 gene. Together with the previously reported patients mentioned above, we demonstrated the role of the PRKD1 variant in brain calcification. We propose that PRKD1 and two genes, ITGB2 and JAM2, which are known to be associated with brain calcification, act through a common signaling pathway abnormality. In support of our hypothesis, there are some experimental results that link PRKD1 and JAM2. PRKD1 functions with the integrin ITGB2 as a partner. JAM2, which is associated with brain calcification and is critical for maintaining of the tight junction of the endothelial cells, interacts with integrins including ITGB2. Therefore, PRKD1 could lead to the pathological phenotype of brain calcification.

DOI： 10.1016/j.ejmg.2024.104992

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DOI： 10.1111/ped.15893

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：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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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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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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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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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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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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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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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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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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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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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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：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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Other Link： https://www.nature.com/articles/s41439-023-00244-x

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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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DOI： 10.1111/cga.12506

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DOI： 10.1111/cga.12500

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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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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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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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DOI： 10.1093/rheumatology/keac130

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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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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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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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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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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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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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DOI： 10.1002/ajmg.a.62531

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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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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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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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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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Language：Japanese   Publisher：(一社)日本小児栄養消化器肝臓学会  

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DOI： 10.1016/j.seizure.2021.05.016

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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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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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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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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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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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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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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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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

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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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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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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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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DOI： 10.1038/s41439-021-00136-y

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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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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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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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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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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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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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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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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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DOI： 10.1002/ajmg.a.61892

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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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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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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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DOI： 10.1097/MPH.0000000000001834

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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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DOI： 10.1002/ajmg.a.61598

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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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DOI： 10.1038/s41439-020-0094-2

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DOI： 10.1002/ajmg.a.61373

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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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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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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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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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DOI： 10.1002/ajmg.a.61356

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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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Subsets of mitochondrial transfer RNA (tRNA) contain the N6 -isopentenyladenosine (i6 A) or 2-methylthio-N6 -isopentenyladenosine (ms2 i6 A) modification at position A37, which is adjacent to an anticodon. These modifications are essential for efficient protein translation in mitochondria and contribute to energy metabolism. The first step in i6 A and ms2 i6 A modifications is catalyzed by tRNA isopentenyltransferase, which is encoded by the TRIT1 gene. Herein, we report a girl with a developmental delay, frequent episodes of seizures induced by febrile illness, and myoclonic epilepsy who had compound heterozygous missense mutations in TRIT1. A mass spectrometry analysis of RNA nucleoside obtained from the subject's peripheral blood and urine showed a marked decrease in both i6 A and ms2 i6 A modifications. These results suggest that the mitochondrial disorder was caused by defective tRNA isopentenylation arising from a loss-of-function mutation in TRIT1. Furthermore, the present observations suggest that noninvasive biochemical analysis using peripheral blood and urine samples are sufficient for the diagnosis of TRIT1-related disorders, making muscle biopsy for the direct measurement of oxidative phosphorylation unnecessary. Such biochemical analyses before the start of antiepileptic medications would be beneficial to avoid hepatotoxicity in patients with possible mitochondrial disorders.

DOI： 10.1002/ajmg.a.61211

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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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Phosphatase and tensin homolog (PTEN) plays an important role in tumor suppression. A germline mutation in the PTEN gene induces not only PTEN hamartoma tumor syndrome, including Cowden syndrome, but also macrocephaly/autism syndrome. Here, we describe a boy with macrocephaly/autism syndrome harboring a novel missense heterozygous PTEN mutation, c.959T>C (p.Leu320Ser). Interestingly, a previously reported nonsense mutation resulting in p.Leu320X was found in Cowden syndrome patients. Our case may be suggestive of a genotype-phenotype correlation.

DOI： 10.1038/s41439-019-0056-8.

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© 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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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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The combined phenotype of thrombocytopenia accompanied by intellectual disability in patients with a de novo heterozygous mutation, i.e., p.Tyr64Cys in CDC42, signifies a clinically recognizable novel syndrome that has been eponymized as "Takenouchi-Kosaki syndrome" (OMIM #616737). In the present study, a detailed phenotypic analysis performed for a total of five patients with Takenouchi-Kosaki syndrome revealed that intellectual disability, macrothrombocytopenia, camptodactyly, structural brain abnormalities with sensorineural deafness, hypothyroidism, and frequent infections comprise the cardinal features of this condition. A morphologic analysis of platelets derived from three affected individuals was performed using electron microscopy. The platelets of the three patients were large and spherical in shape. Furthermore, platelet α-granules were decreased, while vacuoles were increased. We further performed a functional analysis of p.Tyr64Cys in CDC42 through CRISPR/Cas9-mediated gene editing in a Caenorhabditis elegans model. This functional analysis suggested that the mutant allele has hypomorphic effects. Takenouchi-Kosaki syndrome is clinically recognizable by the combined phenotype of intellectual disability, macrothrombocytopenia, camptodactyly, structural brain abnormalities with sensorineural deafness, hypothyroidism, and frequent infections as well as the identification of a heterozygous de novo mutation in CDC42, i.e., p.Tyr64Cys.

DOI： 10.1038/s41598-019-40988-7

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DOI： 10.1016/j.ejmg.2018.06.003

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© 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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<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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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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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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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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DOI： 10.1002/ajmg.a.38703

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DOI： 10.1016/j.ejmg.2017.12.004

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier B.V.  

DOI： 10.1016/j.braindev.2017.06.009

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Among the many regulators of microRNA formation, Argonaute 1 (AGO1) plays critical roles in RNA interference, which controls a wide range of biological activities. Recent large-scale genomic studies have identified at least five patients with intellectual disability/autism spectrum disorder who had de novo mutations in AGO1, but detailed clinical information was not available. The recognizable clinical features that are associated with AGO1 mutations remain to be determined. The proposita was a 15-year-old girl with diffuse hypotonia, infrequent seizures, and intellectual disability with an intelligence quotient of 41. She had characteristic facial features consisting of telecanthus, wide nasal bridge with bulbous nasal tip, and a round face with downslanted palpebral fissures. Serial computed tomography scans showed progressive calcification in the globus pallidus that became evident during childhood. A whole exome analysis in trio revealed a de novo heterozygous mutation in AGO1, i.e., c.595G > A p.(Gly199Ser). The distinctive facial features, i.e., telecanthus, wide nasal bridge with bulbous nasal tip, and a round face with downslanted palpebral fissures, closely resembled previously reported patients who had a chromosomal microdeletion encompassing AGO1 locus. The combinatory phenotype of such characteristic facial features and radiographic features, i.e. progressive calcification in the globus pallidus, in the presently reported patient suggest that AGO1 mutations lead to a syndromic form of intellectual disability/autism spectrum disorder. Distinctive facial features with early and progressive calcification in the globus pallidus may be suggestive of the presence of AGO1 mutations.

DOI： 10.1016/j.ejmg.2018.09.004.

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NCOR1 (nuclear receptor corepressor 1) is a transcriptional coregulatory protein that regulates the balance between histone acetylation and histone deacetylation. NCOR1 is listed as one of the 3,230 dose-sensitive genes which very rarely show truncating mutations in the pediatric population without severe diseases, even in a heterozygous state. In a large cohort study of intellectual disability/autism spectrum disorder, splicing mutations were identified in two individuals, however, the truncating effects of these splicing mutations have not been examined at the transcription level. We describe a 3-year-old girl who had behavior consistent with autism spectrum disorder, a bifid uvula, and early-onset scoliosis. Trio exome analysis showed a de novo heterozygous mutation at the splice donor site in exon 19 of NCOR1, c.2182 + 1G > T (NM_00190440.1). Reverse transcription polymerase chain reaction assay confirmed that the splicing mutation results in skipping of exon 19, a shift in the reading frame and then to nonsense-mediated mRNA decay. This patient represents the first patient who has had unequivocal documentation of haploinsufficient for the NCOR1 gene. Based on our observations, we conclude that NCOR1 is indeed a human disease-causing gene. We further suggest that bifid uvula, a micro form of cleft palate, may well be causally related to de novo NCOR1 haploinsufficiency, in that a previously reported deletion mapping study of atypical Smith-Magenis syndrome patients with large deletions and cleft palate identified that NCOR1, the only loss-of-function-intolerant gene within the region, is located in the smallest region of overlap.

DOI： 10.1002/ajmg.a.40354.

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Therapeutic hypothermia following neonatal encephalopathy is neuroprotective. However, approximately one in two cooled infants still die or develop permanent neurological impairments. Further understanding of variables associated with the effectiveness of cooling is important to improve the therapeutic regimen. To identify clinical factors associated with short-term outcomes of cooled infants, clinical data of 509 cooled infants registered to the Baby Cooling Registry of Japan between 2012 and 2014 were evaluated. Independent variables of death during the initial hospitalization and survival discharge from the cooling hospital at ≤28 days of life were assessed. Death was associated with higher Thompson scores at admission (p < 0.001); higher heart rates after 3-72 hours of cooling (p < 0.001); and higher body temperature after 24 hours of cooling (p = 0.002). Survival discharge was associated with higher 10 minutes Apgar scores (p < 0.001); higher blood pH and base excess (both p < 0.001); lower Thompson scores (at admission and after 24 hours of cooling; both p < 0.001); lower heart rates at initiating cooling (p = 0.003) and after 24 hours of cooling (p < 0.001) and lower average values after 3-72 hours of cooling (p < 0.001); higher body temperature at admission (p < 0.001); and lower body temperature after 24 hours and lower mean values after 3-72 hours of cooling (both p < 0.001). Survival discharge was best explained by higher blood pH (p < 0.05), higher body temperature at admission (p < 0.01), and lower body temperature and heart rate after 24 hours of cooling (p < 0.01 and <0.001, respectively). Lower heart rate, higher body temperature at admission, and lower body temperature during cooling were associated with favorable short-term outcomes.

DOI： 10.1089/ther.2018.0019.

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DOI： 10.1002/humu.23307

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：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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Abstract

The NF1 tumor suppressor gene encodes neurofibromin and is a functional Ras GTPase-activating protein (RasGAP) involved in negatively regulating the Ras signal by accelerating the conversion of activated Ras-GTP to inactive Ras-GDP. NF1 gene germline mutations cause Neurofibromatosis type 1 (NF1, von Recklinghausen disease). We hypothesized that additional genetic alterations promote the malignancy of NF1-associated tumors. To test our hypothesis, we inoculated a GFP-labeled human NF1-deficient cell line, sNF96.2-GFP, which has a frame-shift mutation (c.3683delC, p.Asn1229MetfsTer11) in the NF1 gene, into the renal sub-capsules of immunodeficient mice. A subclonal cell line, the A-1 cell, was established from the developed tumor. We found that A-1 cells show much higher tumorigenic activity and phosphorylation status of MEK and Akt than the parental sNF96.2-GFP cells. We analyzed the genomic DNA of both the sNF96.2 and the A-1 cells by using the next-generation sequencing and our medical exome panel of 4813 genes, which are known to be responsible for most human genetic disorders. We identified 18 heterozygous variants within coding regions of 17 genes that were present in the A-1 cells, but not in the original sNF96.2 cells. We found a single base substitution (c.1508G&amp;gt;T, p.Gly503Val) in the PTPN11 gene, which encodes the tyrosine phosphatese SHP-2, and is associated with the regulation of the Ras signaling pathway. It is critical to note that constitutional gain-of-function mutations in the PTPN11 gene cause Noonan Syndrome in humans due to activation of the Ras pathway. To determine the role of PTPN11 mutation in NF1-associated tumors, we established a cell line overexpressing PTPN11mut in sNF96.2-GFP cells. We inoculated parental cells and PTPN11mut cells into the subcutaneous of nude mice, and we found that PTPN11mut cells show much higher tumorigenic activity than the parental sNF96.2-GFP cells. Our data suggests that this additional gene mutation in PTPN11 promotes the malignant characteristics of NF1-associated tumors.

Citation Format: Yoshimi Arima, Ritsuko Harigai, Ryo Sato, Toshiki Takenouchi, Kenjiro Kosaki, Hideyuki Saya. Additional mutation in PTPN11 gene promotes tumorigenesis of the NF1 gene mutated cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3418. doi:10.1158/1538-7445.AM2017-3418

DOI： 10.1158/1538-7445.am2017-3418

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DOI： 10.1002/ajmg.a.38126

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DOI： 10.1016/j.ajhg.2017.05.006

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<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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DOI： 10.1002/ajmg.a.38167

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DOI： 10.1111/ped.13216

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DOI： 10.1038/srep39508

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DOI： 10.1002/ajmg.a.38363

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We report a 10-year-old girl with Bardet-Biedl syndrome caused by a novel mutation in the Bardet-Biedl syndrome 10 (BBS10) gene. She had multiple malformations, including a dysmorphic face, postaxial polydactyly, polycystic kidney and amblyopia. She presented with typical BBS features, including intellectual disability with emotional outbursts and mild obesity. Whole-exome sequencing identified compound heterozygous mutations with NM_024685.3:c.1677C>A [p.(Tyr559*)] and c.1974T>G [p.(Tyr658*)]. To our knowledge, the latter mutation has never been reported previously.

DOI： 10.1038/hgv.2017.33

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<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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DOI： 10.1002/ajmg.a.37861

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DOI： 10.1002/ajmg.a.36947

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Language：Japanese   Publisher：日本レックリングハウゼン病学会  

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DOI： 10.1016/j.pediatrneurol.2014.09.022

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DOI： 10.1002/ajmg.a.36823

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DOI： 10.1089/ther.2014.0015

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

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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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「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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【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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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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Total pages：70   Responsible for pages：589-594   Language：Japanese Book type：Scholarly book

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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Responsible for pages：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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Responsible for pages：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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Total pages：xxi, 631p   Language：Japanese

CiNii Books

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Total pages：365   Responsible for pages：121   Language：Japanese

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Responsible for pages：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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Responsible for pages：1763-1771   Language：Japanese

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Responsible for pages：1725-1732   Language：Japanese

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-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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Responsible for pages：811-815  

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Responsible for pages：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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Responsible for pages：128-133  

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Total pages：231p   Language：Japanese

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Responsible for pages：519-520  

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Responsible for pages：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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Responsible for pages：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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Total pages：冊   Language：Japanese

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Responsible for pages：1167-1173  

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Total pages：xvi, 887p   Language：Japanese

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Responsible for pages：240-241  

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「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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Total pages：xiv, 350 p.   Responsible for pages：27-45   Language：English

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Responsible for pages：1697-1702  

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Responsible for pages：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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Total pages：150p   Language：Japanese

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Total pages：143p   Language：Japanese

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Responsible for pages：1428-1433   Language：Japanese

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Total pages：170   Language：Japanese

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Responsible for pages：1260-1264   Language：Japanese Book type：Scholarly book

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Language：Japanese   Publisher：(一社)日本周産期・新生児医学会  

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Language：Japanese   Publisher：(一社)日本てんかん学会  

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Language：Japanese   Publisher：(公社)日本小児科学会  

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Language：Japanese   Publisher：日本小児呼吸器学会  

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Language：Japanese   Publisher：日本小児呼吸器学会  

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Language：Japanese   Publisher：(一社)日本周産期・新生児医学会  

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Language：Japanese   Publisher：(一社)日本周産期・新生児医学会  

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Language：Japanese   Publisher：(一社)日本周産期・新生児医学会  

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Language：Japanese   Publisher：(一社)日本周産期・新生児医学会  

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Language：Japanese   Publisher：(一社)日本周産期・新生児医学会  

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Language：Japanese   Publisher：(一社)日本周産期・新生児医学会  

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Language：Japanese   Publisher：(一社)日本周産期・新生児医学会  

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Language：Japanese   Publisher：(一社)日本周産期・新生児医学会  

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Language：Japanese   Publisher：(一社)日本小児神経学会  

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Language：Japanese   Publisher：(株)診断と治療社  

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Language：Japanese   Publisher：(一社)日本小児神経学会  

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Language：Japanese   Publisher：(一社)日本小児神経学会  

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Language：Japanese   Publisher：(一社)日本小児神経学会  

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Language：Japanese   Publisher：(一社)日本小児神経学会  

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Language：Japanese   Publisher：(一社)日本小児神経学会  

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Language：Japanese   Publisher：(一社)日本小児神経学会  

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Language：Japanese   Publisher：(一社)日本周産期・新生児医学会  

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Language：Japanese   Publisher：(公社)日本小児科学会  

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Language：Japanese   Publisher：(公社)日本小児科学会  

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Language：Japanese   Publisher：(公社)日本小児科学会  

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Language：Japanese   Publisher：(公社)日本小児科学会  

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Language：Japanese   Publisher：日本レックリングハウゼン病学会  

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Language：Japanese   Publisher：(公社)日本新生児成育医学会  

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Language：Japanese   Publisher：(公社)日本小児科学会  

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Language：Japanese   Publisher：(公社)日本小児科学会  

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Language：Japanese   Publisher：(公社)日本小児科学会  

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Language：Japanese   Publisher：(公社)日本小児科学会  

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Language：Japanese   Publisher：(株)東京医学社  

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Language：English   Publisher：(一社)日本血液学会  

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Language：Japanese   Publisher：(株)医学書院  

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Language：Japanese   Publisher：(一社)日本周産期・新生児医学会  

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Other Link： 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

Language：Japanese   Publisher：(公社)日本小児科学会  

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Language：Japanese   Publisher：(一社)日本小児神経学会  

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Language：Japanese   Publisher：(一社)日本周産期・新生児医学会  

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Language：Japanese   Publisher：(一社)日本周産期・新生児医学会  

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Language：Japanese   Publisher：(一社)日本周産期・新生児医学会  

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Language：Japanese   Publisher：(一社)日本周産期・新生児医学会  

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Language：Japanese   Publisher：(一社)日本周産期・新生児医学会  

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Language：Japanese   Publisher：(一社)日本周産期・新生児医学会  

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Language：Japanese   Publisher：(一社)日本遺伝カウンセリング学会  

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Language：Japanese   Publisher：(一社)日本小児神経学会  

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Language：Japanese   Publisher：(一社)日本小児神経学会  

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Language：Japanese   Publisher：(一社)日本小児神経学会  

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Language：Japanese   Publisher：(一社)日本小児神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(公社)日本小児科学会  

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Language：Japanese   Publisher：(公社)日本小児科学会  

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Language：Japanese   Publisher：(公社)日本小児科学会  

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Language：Japanese   Publisher：(公社)日本小児科学会  

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Language：English   Publisher：(一社)日本小児神経学会  

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Other Link： 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

Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(公社)日本小児科学会  

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Language：Japanese   Publisher：(一社)日本てんかん学会  

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Language：Japanese   Publisher：医歯薬出版(株)  

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Other Link： 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

Language：Japanese   Publisher：(一社)日本遺伝カウンセリング学会  

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Language：Japanese   Publisher：(株)東京医学社  

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Other Link： 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

Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(一社)日本小児神経学会  

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Language：Japanese   Publisher：(一社)日本小児神経学会  

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