Journal of Human Genetics最新文献

{"title":"Two-decade trends in prenatal genetic testing in Japan.","authors":"Aiko Sasaki, Takahiro Yamada, Haruhiko Sago, Nahoko Shirato, Akihiko Sekizawa, Kenichiro Hata, Hideaki Masuzaki, Yuko Masuzawa, Toshiyuki Yamamoto, Hiroshi Yoshihashi, Shiro Tanaka, Yuka Shibata, Kanako Koike Fukushima, Kenjiro Kosaki, Shigehito Yamada, Masakazu Nishigaki, Ikuo Konishi, Hidehiko Miyake","doi":"10.1038/s10038-026-01465-y","DOIUrl":"https://doi.org/10.1038/s10038-026-01465-y","url":null,"abstract":"<p><p>Prenatal genetic testing in Japan has undergone major changes over the past 2 decades. Maternal serum screening (MSS), amniocentesis (AC), and chorionic villus sampling (CVS) have been the principal tools used to identify fetal chromosomal abnormalities. Recently, non-invasive prenatal testing (NIPT) has reshaped clinical decision-making. However, updated national-level data capturing trends in conventional prenatal testing methods are limited. We aimed to assess the current landscape of prenatal genetic testing in Japan. To update the national data, we compiled test volumes from five major high-volume laboratories that analysed prenatal genetic tests and conducted a supplemental nationwide questionnaire-based survey on ultrasound (US)-only screening between 2020 and 2023. Over this period, MSS declined from 34,887 cases in 2018 to 25,553 in 2023, AC from 16,454 in 2014 to 5620 in 2023, and CVS from 2149 in 2015 to 1167 in 2023, whereas US-only screening increased slightly to >10,000 cases annually. The chromosomal abnormality detection rate among AC cases increased from 8% during 2006-2014 to 20.0% in 2023, with trisomy 21 comprising 43.6% of the cases. During the same period, the proportion of mothers aged ≥35 years increased from 14.0% in 2003 to 30.4% in 2023, whereas the proportion of national live births decreased by 35.3%. Thus, declining test volumes cannot be attributed solely to demographic changes but also reflect the influence of NIPT uptake, improved pretest risk stratification, and changing reproductive decision-making supported by expanding genetic counselling. This study provides foundational data for future prenatal genetic testing practices and policies in Japan.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147326236","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":"Expanding the phenotypic spectrum of LAMA2-related disorders: Axonal neuropathy in the absence of muscular dystrophy.","authors":"Mahsa Mohammadi, Mahdieh Rahimoghli, Aida Ghasemi, Ali Asghar Okhovat, Afagh Alavi","doi":"10.1038/s10038-026-01467-w","DOIUrl":"https://doi.org/10.1038/s10038-026-01467-w","url":null,"abstract":"<p><p>The LAMA2 gene encodes the alpha-2 chain of laminin-2, a key component of the basement membrane that maintains muscle fiber stability and integrity. Mutations in this gene are linked with LAMA2-related muscular dystrophies, which includes congenital muscular dystrophy type 1 A (MDC1A) and limb-girdle muscular dystrophy autosomal recessive 23 (LGMDR23). Here, we present two siblings from one of 200 unrelated Iranian Charcot-Marie-Tooth (CMT) families, exhibiting axonal sensorimotor polyneuropathy, without any clinical signs of muscular dystrophy, carrying a homozygous variant in the LAMA2 gene. Following clinical and paraclinical assessments of the patients, genomic DNA was extracted from peripheral blood samples. Whole-exome sequencing (WES) was employed to identify potential genetic variants, and Sanger sequencing was subsequently used to confirm the detected variant. In silico prediction tools were further applied to evaluate the potential pathogenicity and functional impact of the identified variant. A homozygous missense variant in the LAMA2 gene, c.2916 T > G; p.Phe972Leu, was identified and co-segregated with the disease status within the family, whose neurological assessments confirmed axonal sensorimotor polyneuropathy. So far, only two studies have reported LAMA2 variants in patients only manifesting a neuropathy phenotype. None of these studies reported the detailed clinical data of their cases. However, our study provides further evidence of the association between LAMA2 mutations and neuropathy, and includes comprehensive clinical and paraclinical characterization of the affected individuals. Our findings underscore the importance of comprehensive genomic testing in diagnosing neuromuscular disorders and expand the phenotypic spectrum associated with LAMA2 mutations.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147326249","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":"Psychological distress and cancer worry in unaffected relatives undergoing cascade testing with multigene panel testing.","authors":"Kaori Kimura, Takeshi Kuwata, Yumie Hiraoka, Manami Matsukawa, Chikako Tomozawa, Miki Aitani, Yu Komura, Izumi Miki, Masashi Wakabayashi, Yosuke Furui, Hiroki Kondo, Kazumasa Saigoh, Yasuko Yamamoto, Kiwamu Akagi, Hiroto Narimatsu, Megumu Yokono, Shinsuke Amano, Kaori Muto, Fuji Nagami, Kazuto Kato, Riu Yamashita, Issei Imoto, Shinji Kosugi, Makoto Hirata, Takayuki Yoshino, Yoshiaki Nakamura","doi":"10.1038/s10038-026-01464-z","DOIUrl":"https://doi.org/10.1038/s10038-026-01464-z","url":null,"abstract":"<p><p>Multigene panel testing (MGPT) is increasingly used for diagnosing hereditary cancers; however, its application in cascade testing remains limited, and the psychological impact on unaffected relatives is not well understood. This multicenter study in Japan recruited 123 first-degree relatives without a personal history of cancer to evaluate psychological responses before (T0) and two weeks after (T1) MGPT result disclosure. Participants completed the Japanese version of the Cancer Worry Scale (CWS-J) at both time points and the Impact of Event Scale-Revised (IES-R) at T1. Two weeks after disclosure, 6.5% of relatives met the threshold for clinically significant distress. Mean IES-R scores were higher among carriers of pathogenic variants (mean 8.2) than among those with negative results (mean 4.8) or variants of uncertain significance (mean 2.4). In contrast, multivariate analysis revealed no independent association between test result and post-disclosure distress. In contrast, higher baseline CWS-J scores were strongly associated with elevated IES-R scores after disclosure (p < 0.001). Children and relatives who frequently discussed cancer risk within their families exhibited higher distress levels than other subgroups. Overall, CWS-J scores showed no significant change from pre- to post-disclosure, with 41% of relatives maintaining persistently high worry. Across both time points, unaffected relatives consistently reported lower CWS-J scores than individuals with cancer (p < 0.0001). These findings suggest that MGPT has minimal psychological impact on unaffected relatives undergoing cascade testing, although those with higher preexisting cancer worry may require additional psychosocial support.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147326260","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":"Glycan-related genes and genetic disorders.","authors":"Akira Togayachi, Kiyohiko Angata, Shoko Nishihara","doi":"10.1038/s10038-026-01463-0","DOIUrl":"10.1038/s10038-026-01463-0","url":null,"abstract":"<p><p>Glycosylation is a ubiquitous and essential post-translational modification in biological systems. Most cell-surface and secreted proteins are glycosylated: the glycans contribute to the structural integrity of proteins and cell membranes, and are involved in numerous physiological functions from cell-cell communication and modulation of extracellular signals to immune response and tissue development. The vast array of N-linked, O-linked, and proteoglycan-type glycans are synthesized in a stepwise manner through the coordinated action of numerous glycosyltransferases and glycosidases encoded by \"glycogenes\". At present, more than 400 glycogenes are involved in glycan biosynthesis in humans. Given the essential roles of glycosylation, it is not surprising that mutations in glycogenes cause various genetic disorders, collectively referred to as congenital disorders of glycosylation (CDGs). However, directly linking specific gene mutations to altered glycan structures and resulting clinical symptoms remains a significant challenge because the biological functions are mediated not by the enzymes themselves, but by the diverse glycan structures that they generate. Many undiagnosed rare diseases are suspected to result from defects in genes involved in glycosylation pathways. Furthermore, reports of newly identified types of CDGs are steadily increasing. Comprehensive understanding of these disorders requires a multidisciplinary approach integrating genetics, biochemistry, glycomics, and clinical research. In this review, we first describe glycans, including the different types and their biological functions. Next, all of the glycogenes involved in various synthetic pathways are presented, followed by examples of genetic disorders caused by their mutation and the glycogenomic approaches used to explore them.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147307002","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":"Vacuolar myopathy caused by CASQ1 p.Asp244His: pathogenic evidence from two unrelated Chinese families.","authors":"Xingyu Xia, Milla Laarne, Tonglin Pan, Kexin Jiao, Nachuan Cheng, Bochen Zhu, Meining Diao, Mingshi Gao, Ying Liu, Chongbo Zhao, Zhe Zhao, Wenhua Zhu","doi":"10.1038/s10038-026-01461-2","DOIUrl":"https://doi.org/10.1038/s10038-026-01461-2","url":null,"abstract":"<p><p>Calsequestrin-1 (CASQ1)-related myopathy is a rare skeletal muscle disorder caused by mutations in CASQ1 gene, which encodes a major calcium-buffering protein of the sarcoplasmic reticulum (SR). It is characterized histopathologically by tubular aggregates or optically empty vacuoles, predominantly affecting type II muscle fibers. In this study, we report two unrelated Chinese patients presenting with late-onset, slowly progressive muscle weakness, fatigue, and myalgia. Both had mildly to moderately elevated serum creatine kinase levels. Muscle biopsies revealed typical optically empty vacuoles primarily in type II fibers. Whole-exome sequencing identified an identical heterozygous CASQ1 variant, c.730G > C (p.Asp244His), located at a highly conserved residue. In vitro expression of the mutant CASQ1 in HeLa cells confirmed its aggregation tendency, suggesting impaired protein folding or calcium handling. Immunofluorescence revealed abnormal aggregation of CASQ1 protein around the edge of vacuoles, co-localized with SQSTM1/p62, and the endoplasmic reticulum (ER) stress marker PERK. Our findings support the pathogenic role of the p.Asp244His variant and provide further insights into CASQ1-related myopathy in Asian populations.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146207241","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":"Clinical and genetic characteristics of a large cohort of children with Alagille syndrome: identification of 57 new variants in the JAG1 gene.","authors":"Elena A Gusarova, Anna V Degtyareva, Alla E Lavrova, Tatiana V Strokova, Natalia A Semenova, Ekaterina Y Nuzhnaya, Marina S Gautier, Elena A Filippova, Ekaterina S Shubina, Medan K Isaeva, Eleonora A Annenkova, Victoria Y Bezverbnaya, Yana D Nazarenko, Ekaterina Y Konovalova, Elena Y Borisova, Andrey V Marakhonov, Ekaterina Y Zakharova","doi":"10.1038/s10038-026-01462-1","DOIUrl":"https://doi.org/10.1038/s10038-026-01462-1","url":null,"abstract":"<p><p>Alagille syndrome (ALGS) is an inherited multisystem disorder with a broad phenotypic spectrum and no apparent genotype-phenotype correlation. This study aimed to present the clinical and genetic characteristics of 115 patients diagnosed with ALGS in the Russian Federation between 2010 and 2023. The most common pathogenic variants identified in the study cohort were c.2122_2125delCAGT p.(Gln708Valfs*34) and c.439+1G>A. Two previously undescribed JAG1 variants, c.247C>T p.(Gln83Ter) and c.1188del p.(Phe396Leufs*16), were assessed in silico as likely pathogenic. Functional analysis of four JAG1 variants (c.439+1G>A, c.1120+5G>A, c.886+3A>G, and c.1156G>A) and one NOTCH2 variant (c.1264+5G>A) using a minigene splicing assay classified them as pathogenic splice-site variants.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146194642","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":"Childhood-onset ataxia with dystonia: expanding the spectrum of VWA3B-related disorders.","authors":"Naik Adarsha, Pradip Paria, Amita Moirangthem","doi":"10.1038/s10038-026-01460-3","DOIUrl":"https://doi.org/10.1038/s10038-026-01460-3","url":null,"abstract":"<p><p>Hereditary cerebellar ataxias are a group of rare genetic disorders that affect coordination, balance, and speech. Childhood-onset forms can be especially severe and difficult to diagnose. The VWA3B gene, though not fully understood, plays a role in brain development and has been linked to autosomal recessive spinocerebellar ataxia type 22 (SCAR22), an adult-onset cerebellar ataxia with variable features. A single family with 3 affected adults has been described to date. We report a 1 year 9 months old boy with early-onset neuroregression and ataxia. Prominent dystonia involving the limbs and eyelids (blepharospasm) was also a novel feature observed in him. Exome sequencing revealed compound heterozygous variants in VWA3B. Unlike the previous report describing a missense variant, our patient had nonsense and frameshift variants. This case highlights the expanding clinical and genotypic spectrum of VWA3B-related ataxia.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146165479","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":"Modern descendants of Kyordyughen warrior (Yakutia, 4200 years before present) in populations of Far East.","authors":"Dmitry Adamov, Maxat Zhabagin, Elena Balanovska","doi":"10.1038/s10038-026-01459-w","DOIUrl":"https://doi.org/10.1038/s10038-026-01459-w","url":null,"abstract":"<p><p>A search for the modern descendants of the Neolithic population has been conducted using two datasets of Y-chromosome polymorphisms: literature data on the ancient population of Northeast Eurasia and our own data on 256 whole genomes of 11 indigenous peoples of the Russian Far East (Aleuts, Chukchi, Evens, Evenks, Itelmens, Koryaks, Nanais, Negidals, Nivkhs, Orochi, and Ulchi). Y-SNP analysis revealed that both Kyordyughen I (4200 YBP) and Kyordyughen II (4600 YВР) samples of the Yakutian Late Neolithic belong to the haplogroup N-L708 and lie on its two branches that diverged at 6200 YBP. A quarter (67 of 256) of the analysed samples, including Chukchi, Evens, Evenks, Itelmens, Koryaks, Nanais, Nivkhs, Orochi, and Ulchi, belong to the haplogroup N-L708 and are, to various extents, genetically related to the Neolithic Yakutian individuals. The most direct descendants of the famous Kyordyughen warrior (Kyordyughen I) are the indigenous peoples of Kamchatka and Chukotka (Chukchi, Koryaks, Evens). The divergence time of their Y-lineages (4300 ± 1000 YВР) is consistent with the radiocarbon dates for Kyordyughen I. Literary data on Y-STR polymorphism suggest that descendants of the Kyordyughen warrior dispersed far across North Asia. Ancient N-L708 carriers started to expand from Transbaikalia across Northeast Eurasia at ~7000 YBP. About 4000-3000 YВР, the lineages close to the Kyordyughen samples arrived in today's Krasnoyarsk territory, Yakutia, Mongolia and Chukotka. Our findings are in good agreement with archaeological data and the autosomal genome-based modelling of the Kyordyughen warrior's origin.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146142523","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":"Development of a zebrafish model of Loeys-Dietz syndrome through tgfbr2b knockdown.","authors":"Rie Chida, Genri Kawahara, Mami Nakayashiki, Hisashi Kawashima, Gaku Yamanaka, Yukiko K Hayashi","doi":"10.1038/s10038-026-01457-y","DOIUrl":"https://doi.org/10.1038/s10038-026-01457-y","url":null,"abstract":"<p><p>Loeys-Dietz syndrome (LDS), an autosomal dominant connective tissue disorder, was initially considered \"atypical\" Marfan syndrome (MFS). MFS is caused by mutations in FBN1 encoding fibrillin 1, which binds to transforming growth factor β (TGF-β) to inhibit it from binding to TGF-β receptors. In contrast, LDS is caused by mutations in TGF-β-related genes, including TGFBR2. Some clinical symptoms of LDS, including cardiovascular and skeletal complications, are similar to those observed in MFS; however, arterial tortuosity and widespread aortic aneurysm, hypertelorism, and cleft palate or bifida uvula are specific to LDS. Therefore, the role and difference of the TGF-β signaling pathway in LDS remains unclear. To elucidate the pathological mechanisms of LDS and the phenotypical differences between MFS and LDS, an LDS zebrafish model was established by knocking down tgfbr2b using an antisense morpholino oligonucleotide (tgfbr2b morphant), and the phenotype and expression of genes and proteins related to the TGF-β signaling pathway were investigated. tgfbr2b morphants presented with a dysmorphic face, bent body, and cardiovascular abnormalities, some of which were similar to those observed in patients with LDS. The TGF-β1 gene and protein expression, as well as the genes related to the BMP signaling pathway, were upregulated, and the smad1/5/9 protein exhibited enhanced phosphorylation. These results suggest that dysregulation of BMP signaling during development plays an essential role in the craniofacial dysmorphism and cardiac abnormalities observed in the LDS zebrafish model. Our study clarified the differences of pathological mechanism between MFS and LDS.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146105947","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":"Acknowledgment to the reviewers in 2025","authors":"Toshihiro Tanaka","doi":"10.1038/s10038-026-01456-z","DOIUrl":"10.1038/s10038-026-01456-z","url":null,"abstract":"","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"71 4","pages":"185-186"},"PeriodicalIF":2.5,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s10038-026-01456-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146064272","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}