Journal of Human Genetics最新文献

{"title":"CRYAB stop-loss variant causes rare syndromic dilated cardiomyopathy with congenital cataract: expanding the phenotypic and mutational spectrum of alpha-B crystallinopathy","authors":"Changhee Ha, Darae Kim, Minjung Bak, Jong-Ho Park, Young-gon Kim, Ja-Hyun Jang, Jong-Won Kim, Jin-Oh Choi, Mi-Ae Jang","doi":"10.1038/s10038-023-01218-1","DOIUrl":"10.1038/s10038-023-01218-1","url":null,"abstract":"Missense mutations in the alpha-B crystallin gene (CRYAB) have been reported in desmin-related myopathies with or without cardiomyopathy and have also been reported in families with only a cataract phenotype. Dilated cardiomyopathy (DCM) is a disorder with a highly heterogeneous genetic etiology involving more than 60 causative genes, hindering genetic diagnosis. In this study, we performed whole genome sequencing on 159 unrelated patients with DCM and identified an unusual stop-loss pathogenic variant in NM_001289808.2:c.527A>G of CRYAB in one patient. The mutant alpha-B crystallin protein is predicted to have an extended strand with addition of 19 amino acid residues, p.(Ter176TrpextTer19), which may contribute to aggregation and increased hydrophobicity of alpha-B crystallin. The proband, diagnosed with DCM at age 32, had a history of bilateral congenital cataracts but had no evidence of myopathy or associated symptoms. He also has a 10-year-old child diagnosed with bilateral congenital cataracts with the same CRYAB variant. This study expands the mutational spectrum of CRYAB and deepens our understanding of the complex phenotypes of alpha-B crystallinopathies.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 3-4","pages":"159-162"},"PeriodicalIF":3.5,"publicationDate":"2024-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139424949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"C-terminal truncations in IQSEC2: implications for synaptic localization, guanine nucleotide exchange factor activity, and neurological manifestations","authors":"Moeko Nakashima, Tomoko Shiroshima, Masahiro Fukaya, Takeyuki Sugawara, Hiroyuki Sakagami, Kazuki Yamazawa","doi":"10.1038/s10038-023-01210-9","DOIUrl":"10.1038/s10038-023-01210-9","url":null,"abstract":"IQSEC2 gene on chromosome Xq11.22 encodes a member of guanine nucleotide exchange factor (GEF) protein that is implicated in the activation of ADP-ribosylation factors (Arfs) at the postsynaptic density (PSD), and plays a crucial role in synaptic transmission and dendritic spine formation. Alterations in IQSEC2 have been linked to X-linked intellectual developmental disorders including epilepsy and behavioral abnormalities. Of interest, truncating variants at the C-terminus of IQSEC2 can cause severe phenotypes, akin to truncating variants located in other regions. Here, we present a 5-year-old boy with severe intellectual disability and progressive epilepsy. The individual carried a nonsense variant p.Q1227* in the last exon of the IQSEC2 gene that was supposed to escape nonsense-mediated mRNA decay, thereby leading to a translation of C-terminus truncated IQSEC2 protein with residual activity. The functional analyses showed that the GEF activity of IQSEC2 Q1227* was compromised, and that the IQSEC2 Q1227* lacked preferential synaptic localization due to the absence of functional domains for binding to scaffolding proteins in the PSD. The impaired GEF activity and disrupted synaptic localization of the mutant IQSEC2 protein could impact dendritic and spine development in neurons, potentially explaining the patient’s severe neurological manifestations. Our findings indicate that C-terminal truncations in IQSEC2, previously not well-characterized, may have significant pathogenic implications.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 3-4","pages":"119-123"},"PeriodicalIF":3.5,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139413203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prediction of protein structure and AI","authors":"Shiho Ohno, Noriyoshi Manabe, Yoshiki Yamaguchi","doi":"10.1038/s10038-023-01215-4","DOIUrl":"10.1038/s10038-023-01215-4","url":null,"abstract":"AlphaFold, an artificial intelligence (AI)-based tool for predicting the 3D structure of proteins, is now widely recognized for its high accuracy and versatility in the folding of human proteins. AlphaFold is useful for understanding structure-function relationships from protein 3D structure models and can serve as a template or a reference for experimental structural analysis including X-ray crystallography, NMR and cryo-EM analysis. Its use is expanding among researchers, not only in structural biology but also in other research fields. Researchers are currently exploring the full potential of AlphaFold-generated protein models. Predicting disease severity caused by missense mutations is one such application. This article provides an overview of the 3D structural modeling of AlphaFold based on deep learning techniques and highlights the challenges in predicting the pathogenicity of missense mutations.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 10","pages":"477-480"},"PeriodicalIF":2.6,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139095842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Carrier screening for present disease prevalence and recessive genetic disorder in Taiwanese population","authors":"Li Shan Chen, Cheng Wei Yu, Wei Jiun Li, Wen Chi Hsieh, Yi Ping Li","doi":"10.1038/s10038-023-01212-7","DOIUrl":"10.1038/s10038-023-01212-7","url":null,"abstract":"Carrier screening is important to people have a higher prevalence of severe recessive or X-linked genetic conditions. This study is aimed that the frequency and uncertain nature of genetic variants was identified in Taiwanese population, providing individuals with information at risk of inherited diseases and their heritability to newborns. A total of 480 subjects receiving genetic counseling with no family history of inherited disorders were recruited into a cohort from 2018 to 2022. Next-generation sequencing (NGS) panel for autosomal dominant (AD), autosomal recessive (AR) and X-linked diseases was sequenced to assess disease prevalence and carrier frequency for the targeted diseases. Publicly available NGS datasets were analyzed following a tier-based system and ACMG recommendation. 5.3% of subjects showed the presence of variants for genetic disorder, and 2.3% of them were determined with AD. 14 of subjects with pathogenic variants were carriers for AR. The inherited genes were LDLR for AD disorders and AR disorders included GAA and ATP7B. 21.6% of subjects had highest carrier frequency of GJB2 gene. 0.5% of subjects had highest frequency of GJB6 for AR condition. In conclusions, the variants in LDLR, GAA and ATP7B genes were identified in Taiwanese population, indicating individuals had higher risk of Pompe disease, Wilson’s disease and familial hypercholesterolemia. Taiwanese individuals carrying GJB2 and GJB6 had the considerable risk of hearing loss passing to their offspring.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 3-4","pages":"115-118"},"PeriodicalIF":3.5,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138885045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An update and frequency distribution of Y chromosome haplogroups in modern Japanese males","authors":"Makoto Inoue, Youichi Sato","doi":"10.1038/s10038-023-01214-5","DOIUrl":"10.1038/s10038-023-01214-5","url":null,"abstract":"Japanese males belong to the Y chromosome C1a1, C2, D1a2a, D1a2a-12f2b, O1b2, O1b2a1a1, O2a2b1, and O2a1b haplogroups. Notably, the regional frequency of each haplogroup is homogeneous. Owing to recent developments in genome sequencing technology, the phylogenetic tree of Y chromosome haplogroups is updated annually. Therefore, in this study, we aimed to provide an update on the Y chromosome haplogroups of modern Japanese males and examine their regional distributions. Using 1,640 samples of Japanese males from seven Japanese cities (Nagasaki, Fukuoka, Tokushima, Osaka, Kanazawa, Kawasaki, and Sapporo), haplogroups C1a1, C2, D1a2a, D1a2a-12f2b, O1b2, and O1b2a1a1 were updated based on the latest phylogenetic tree. Haplogroup C1a1 was mainly classified into C1a1a1a and C1a1a1b subgroups; C1a1a1b was more common in Tokushima and Osaka than in the other regions. Haplogroup C2 was mainly classified into C2a, C2b1a1a, C2b1a1b, C2b1a2, and C2b1b subgroups and exhibited frequency differences in Osaka. Haplogroup D1a2a was classified into D1a2a1c1 and D1a2a2 subgroups, and its frequency varied between Tokushima and Osaka. Haplogroup D1a2a-12f2b was classified into D1a2a1a2b1a1a and D1a2a1a3 subgroups; however, no significant frequency differences were observed. Haplogroup O1b2 was classified into O1b2a1a2a1a, O1b2a1a2a1b, and O1b2a1a3 subgroups, with frequency differences between Nagasaki and Kanazawa. Haplogroup O1b2a1a1 was mainly classified into O1b2a1a1a, O1b2a1a1b, and O1b2a1a1c subgroups; however, no significant frequency differences were observed. Our findings suggest that gene flow in the Kinki region is caused by human migration.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 3-4","pages":"107-114"},"PeriodicalIF":3.5,"publicationDate":"2023-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138826571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNA sequencing and target long-read sequencing reveal an intronic transposon insertion causing aberrant splicing","authors":"Ryota Kawakami, Takuya Hiraide, Kazuki Watanabe, Sachiko Miyamoto, Kota Hira, Kazuyuki Komatsu, Hidetoshi Ishigaki, Kimiyoshi Sakaguchi, Masato Maekawa, Keita Yamashita, Tokiko Fukuda, Isao Miyairi, Tsutomu Ogata, Hirotomo Saitsu","doi":"10.1038/s10038-023-01211-8","DOIUrl":"10.1038/s10038-023-01211-8","url":null,"abstract":"More than half of cases with suspected genetic disorders remain unsolved by genetic analysis using short-read sequencing such as exome sequencing (ES) and genome sequencing (GS). RNA sequencing (RNA-seq) and long-read sequencing (LRS) are useful for interpretation of candidate variants and detection of structural variants containing repeat sequences, respectively. Recently, adaptive sampling on nanopore sequencers enables target LRS more easily. Here, we present a Japanese girl with premature chromatid separation (PCS)/mosaic variegated aneuploidy (MVA) syndrome. ES detected a known pathogenic maternal heterozygous variant (c.1402-5A>G) in intron 10 of BUB1B (NM_001211.6), a known responsive gene for PCS/MVA syndrome with autosomal recessive inheritance. Minigene splicing assay revealed that almost all transcripts from the c.1402-5G allele have mis-splicing with 4-bp insertion. GS could not detect another pathogenic variant, while RNA-seq revealed abnormal reads in intron 2. To extensively explore variants in intron 2, we performed adaptive sampling and identified a paternal 3.0 kb insertion. Consensus sequence of 16 reads spanning the insertion showed that the insertion consists of Alu and SVA elements. Realignment of RNA-seq reads to the new reference sequence containing the insertion revealed that 16 reads have 5’ splice site within the insertion and 3’ splice site at exon 3, demonstrating causal relationship between the insertion and aberrant splicing. In addition, immunoblotting showed severely diminished BUB1B protein level in patient derived cells. These data suggest that detection of transcriptomic abnormalities by RNA-seq can be a clue for identifying pathogenic variants, and determination of insert sequences is one of merits of LRS.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 2","pages":"91-99"},"PeriodicalIF":3.5,"publicationDate":"2023-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138680567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A heterozygous germline deletion within USP8 causes severe neurodevelopmental delay with multiorgan abnormalities","authors":"Masamune Sakamoto, Kenji Kurosawa, Koji Tanoue, Kazuhiro Iwama, Fumihiko Ishida, Yoshihiro Watanabe, Nobuhiko Okamoto, Naomi Tsuchida, Yuri Uchiyama, Eriko Koshimizu, Atsushi Fujita, Kazuharu Misawa, Satoko Miyatake, Takeshi Mizuguchi, Naomichi Matsumoto","doi":"10.1038/s10038-023-01209-2","DOIUrl":"10.1038/s10038-023-01209-2","url":null,"abstract":"Ubiquitin-specific protease 8 (USP8) is a deubiquitinating enzyme involved in deubiquitinating the enhanced epidermal growth factor receptor for escape from degradation. Somatic variants at a hotspot in USP8 are a cause of Cushing’s disease, and a de novo germline USP8 variant at this hotspot has been described only once previously, in a girl with Cushing’s disease and developmental delay. In this study, we investigated an exome-negative patient with severe developmental delay, dysmorphic features, and multiorgan dysfunction by long-read sequencing, and identified a 22-kb de novo germline deletion within USP8 (chr15:50469966-50491995 [GRCh38]). The deletion involved the variant hotspot, one rhodanese domain, and two SH3 binding motifs, and was presumed to be generated through nonallelic homologous recombination through Alu elements. Thus, the patient may have perturbation of the endosomal sorting system and mitochondrial autophagy through the USP8 defect. This is the second reported case of a germline variant in USP8.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 2","pages":"85-90"},"PeriodicalIF":3.5,"publicationDate":"2023-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138460345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A missense variant in EXOSC8 causes exon skipping and expands the phenotypic spectrum of pontocerebellar hypoplasia type 1C","authors":"Maha S. Zaki, Sherif F. Abdel-Ghafar, Mohamed S. Abdel-Hamid","doi":"10.1038/s10038-023-01207-4","DOIUrl":"10.1038/s10038-023-01207-4","url":null,"abstract":"Pontocerebellar hypoplasia (PCH) is a rare heterogeneous neurodegenerative disorder affecting the pons and cerebellum and is currently classified into 17 types (PCH1-PCH17). PCH1 is distinguishable from other types by the association of spinal motor neuron dysfunction. Based on the underlying genetic etiology, PCH1 is further classified into 6 different subtypes (PCH1 A-F). Of them, PCH type 1C is caused by pathogenic variants in EXOSC8 gene and so far, only four families have been described in the literature. In this study, we report a new patient with PCH1 who proved by whole-exome sequencing to harbor a novel homozygous missense variant in the splice region of EXOSC8 gene (c.238 G > A; p.Val80Ile). Studying mRNA of the patient confirmed that this variant results in skipping of exon 5 of the gene and early protein truncation. Our patient presented with the main clinical findings of PCH type 1C including psychomotor retardation, spasticity, spinal muscle atrophy, and respiratory problems. However, unlike most of the reported cases, he did not develop hearing or visual impairment and displayed a longer survival. In addition, our patient had dysmorphic facies, nystagmus, congenital esotropia and contractures which were infrequently described in patients with EXOSC8. Diaphragmatic hernia, dilated lateral ventricles, hypoplastic temporal lobes, and thinning of the brain stem were additional new findings noted in our patient. This study presents the fifth family with this extremely rare type of PCH and expands the associated clinical and brain imaging findings.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 2","pages":"79-84"},"PeriodicalIF":3.5,"publicationDate":"2023-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10810757/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138451588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel missense variants cause intermediate phenotypes in the phenotypic spectrum of SLC5A6-related disorders","authors":"Yasuhiro Utsuno, Keisuke Hamada, Kohei Hamanaka, Keita Miyoshi, Keiji Tsuchimoto, Satoshi Sunada, Toshiyuki Itai, Masamune Sakamoto, Naomi Tsuchida, Yuri Uchiyama, Eriko Koshimizu, Atsushi Fujita, Satoko Miyatake, Kazuharu Misawa, Takeshi Mizuguchi, Yasuhito Kato, Kuniaki Saito, Kazuhiro Ogata, Naomichi Matsumoto","doi":"10.1038/s10038-023-01206-5","DOIUrl":"10.1038/s10038-023-01206-5","url":null,"abstract":"SLC5A6 encodes the sodium-dependent multivitamin transporter, a transmembrane protein that uptakes biotin, pantothenic acid, and lipoic acid. Biallelic SLC5A6 variants cause sodium-dependent multivitamin transporter deficiency (SMVTD) and childhood-onset biotin-responsive peripheral motor neuropathy (COMNB), which both respond well to replacement therapy with the above three nutrients. SMVTD usually presents with various symptoms in multiple organs, such as gastrointestinal hemorrhage, brain atrophy, and global developmental delay, at birth or in infancy. Without nutrient replacement therapy, SMVTD can be lethal in early childhood. COMNB is clinically milder and has a later onset than SMVTD, at approximately 10 years of age. COMNB symptoms are mostly limited to peripheral motor neuropathy. Here we report three patients from one Japanese family harboring novel compound heterozygous missense variants in SLC5A6, namely NM_021095.4:c.[221C>T];[642G>C] p.[(Ser74Phe)];[(Gln214His)]. Both variants were predicted to be deleterious through multiple lines of evidence, including amino acid conservation, in silico predictions of pathogenicity, and protein structure considerations. Drosophila analysis also showed c.221C>T to be pathogenic. All three patients had congenital brain cysts on neonatal cranial imaging, but no other morphological abnormalities. They also had a mild motor developmental delay that almost completely resolved despite no treatment. In terms of severity, their phenotypes were intermediate between SMVTD and COMNB. From these findings we propose a new SLC5A6-related disorder, spontaneously remitting developmental delay with brain cysts (SRDDBC) whose phenotypic severity is between that of SMVTD and COMNB. Further clinical and genetic evidence is needed to support our suggestion.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 2","pages":"69-77"},"PeriodicalIF":3.5,"publicationDate":"2023-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138444897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of potential disease-associated variants in idiopathic generalized epilepsy using targeted sequencing","authors":"Regina Gamirova, Elena Shagimardanova, Takehiro Sato, Takayuki Kannon, Rimma Gamirova, Atsushi Tajima","doi":"10.1038/s10038-023-01208-3","DOIUrl":"10.1038/s10038-023-01208-3","url":null,"abstract":"Many questions remain regarding the genetics of idiopathic generalized epilepsy (IGE), a subset of genetic generalized epilepsy (GGE). We aimed to identify the candidate coding variants of epilepsy panel genes in a cohort of affected individuals, using variant frequency information from a control cohort of the same region. We performed whole-exome sequencing analysis of 121 individuals and 10 affected relatives, focusing on variants of 950 candidate genes associated with epilepsy according to the Genes4Epilepsy curated panel. We identified 168 candidate variants (CVs) in 137 of 950 candidate genes in 88 of 121 affected individuals with IGE, of which 61 were novel variants. Notably, we identified five CVs in known GGE-associated genes (CHD2, GABRA1, RORB, SCN1A, and SCN1B) in five individuals and CVs shared by affected individuals in each of four family cases for other epilepsy candidate genes. The results of this study demonstrate that IGE is a disease with high heterogeneity and provide IGE-associated CVs whose pathogenicity should be proven by future studies, including advanced functional analysis. The low detection rate of CVs in the GGE-associated genes (4.1%) in this study suggests the current incompleteness of the Genes4Epilepsy panel for the diagnosis of IGE in clinical practice.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 2","pages":"59-67"},"PeriodicalIF":3.5,"publicationDate":"2023-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138295294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}