Journal of Human Genetics最新文献_第7页

Vacuolar myopathy caused by CASQ1 p.Asp244His: pathogenic evidence from two unrelated Chinese families CASQ1 p.Asp244His引起的空泡性肌病：来自两个无亲缘关系的中国家庭的致病证据

IF 2.3 3区生物学

Journal of Human Genetics Pub Date : 2026-02-16 DOI: 10.1038/s10038-026-01461-2

Xingyu Xia, Milla Laarne, Tonglin Pan, Kexin Jiao, Nachuan Cheng, Bochen Zhu, Meining Diao, Mingshi Gao, Ying Liu, Chongbo Zhao, Zhe Zhao, Wenhua Zhu

{"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":"10.1038/s10038-026-01461-2","url":null,"abstract":"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.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"71 7","pages":"419-425"},"PeriodicalIF":2.3,"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}

引用次数: 0

Clinical and genetic characteristics of a large cohort of children with Alagille syndrome: identification of 57 new variants in the JAG1 gene 一大群Alagille综合征患儿的临床和遗传特征：鉴定JAG1基因的57个新变体

IF 2.3 3区生物学

Journal of Human Genetics Pub Date : 2026-02-13 DOI: 10.1038/s10038-026-01462-1

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

{"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":"10.1038/s10038-026-01462-1","url":null,"abstract":"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.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"71 7","pages":"427-433"},"PeriodicalIF":2.3,"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}

引用次数: 0

Childhood-onset ataxia with dystonia: expanding the spectrum of VWA3B-related disorders 儿童期发作的共济失调伴张力障碍：扩大了vwa3b相关疾病的范围。

IF 2.3 3区生物学

Journal of Human Genetics Pub Date : 2026-02-12 DOI: 10.1038/s10038-026-01460-3

Naik Adarsha, Pradip Paria, Amita Moirangthem

引用次数: 0

Modern descendants of Kyordyughen warrior (Yakutia, 4200 years before present) in populations of Far East 远东地区Kyordyughen战士（雅库特人，距今4200年前）的现代后裔。

IF 2.3 3区生物学

Journal of Human Genetics Pub Date : 2026-02-09 DOI: 10.1038/s10038-026-01459-w

Dmitry Adamov, Maxat Zhabagin, Elena Balanovska

{"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":"10.1038/s10038-026-01459-w","url":null,"abstract":"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.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"71 7","pages":"413-418"},"PeriodicalIF":2.3,"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}

引用次数: 0

Development of a zebrafish model of Loeys–Dietz syndrome through tgfbr2b knockdown 通过敲低tgfbr2b构建Loeys-Dietz综合征斑马鱼模型。

IF 2.3 3区生物学

Journal of Human Genetics Pub Date : 2026-02-03 DOI: 10.1038/s10038-026-01457-y

Rie Chida, Genri Kawahara, Mami Nakayashiki, Hisashi Kawashima, Gaku Yamanaka, Yukiko K. Hayashi

{"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":"10.1038/s10038-026-01457-y","url":null,"abstract":"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.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"71 7","pages":"405-412"},"PeriodicalIF":2.3,"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}

引用次数: 0

Acknowledgment to the reviewers in 2025 2025年向审稿人致谢。

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2026-01-28 DOI: 10.1038/s10038-026-01456-z

Toshihiro Tanaka

引用次数: 0

Congenital diarrhea/enteropathy due to a novel biallelic PERCC1 variant – a case-based review and variant analysis 先天性腹泻/肠病由于一种新的双等位基因PERCC1变异-基于病例的回顾和变异分析。

IF 2.3 3区生物学

Journal of Human Genetics Pub Date : 2026-01-23 DOI: 10.1038/s10038-026-01455-0

Aaqib Zaffar Banday, Ishaq Malik, Anit Kaur, Rohit Sadanand, Wasim Yousuf Thoker, Usman Muzafar Jan, Altaf Hussain Kambay, Abdus Sami Bhat

{"title":"Congenital diarrhea/enteropathy due to a novel biallelic PERCC1 variant – a case-based review and variant analysis","authors":"Aaqib Zaffar Banday, Ishaq Malik, Anit Kaur, Rohit Sadanand, Wasim Yousuf Thoker, Usman Muzafar Jan, Altaf Hussain Kambay, Abdus Sami Bhat","doi":"10.1038/s10038-026-01455-0","DOIUrl":"10.1038/s10038-026-01455-0","url":null,"abstract":"Congenital diarrhea/enteropathy due to inherited biallelic defects in the newly discovered gene PERCC1 has been reported in only a few patients thus far. We utilized whole-exome sequencing (WES) to identify a novel PERCC1 stop-gain variant (c.188C>G, p.Ser63*). Literature review identified 16 additional patients – 13 with large biallelic deletions involving the PERCC1 gene and three with a homozygous single-nucleotide (stop-gain) variant (c.390C>G, p.Tyr130*). Median [range] age at onset of diarrhea in patients with available data (including ours) is 9.5 [1–21] days. Chronic intractable diarrhea often results in growth failure, meriting the utilization of parenteral nutrition (PN), especially during the first few years of life. Discontinuation of PN has been reported in six patients at an age of 8 [4–17] years. Our report highlights the role of WES in identifying PERCC1 variants in patients with congenital diarrhea/enteropathy. Thus far, PERCC1 variants have primarily been identified through targeted testing or whole-genome sequencing.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"71 8","pages":"521-524"},"PeriodicalIF":2.3,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146040982","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}

引用次数: 0

A novel homozygous splicing variant in FRA10AC1: further delineation of the phenotype FRA10AC1中一个新的纯合剪接变异：表型的进一步描述。

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2026-01-23 DOI: 10.1038/s10038-025-01447-6

Mohamed S. Abdel-Hamid, Ghada M. H. Abdel-Salam

{"title":"A novel homozygous splicing variant in FRA10AC1: further delineation of the phenotype","authors":"Mohamed S. Abdel-Hamid, Ghada M. H. Abdel-Salam","doi":"10.1038/s10038-025-01447-6","DOIUrl":"10.1038/s10038-025-01447-6","url":null,"abstract":"Biallelic variants in FRA10AC1, encoding a component of the spliceosomal C complex that is crucial for functional mRNA processing, have been recently associated with a neurodevelopmental disorder characterized by developmental delay, variable dysmorphic facies, growth retardation, and corpus callosum abnormalities. Skeletal and congenital heart defects were observed in some patients. To date, only 10 patients from 6 unrelated families with FRA10AC1 variants have been reported in the literature. Herein, we describe a new patient harboring a loss-of-function variant in FRA10AC1. Our patient presented with global developmental delay, hypotonia, dysmorphic facies, hyperactivity, and severe intellectual disability. He had no seizures. Unusual findings noted in the patient were fused kidneys and bilateral cone dystrophy. Brain MRI showed a hypoplastic corpus callosum, delayed myelination, and a small cyst in the caudate nucleus. Exome sequencing revealed a novel homozygous variant in the donor splice site of exon 7 of the FRA10AC1 (c.465+1G>A) as the likely cause of the patient’s phenotype. Thorough investigations of the exome data did not reveal any additional potential pathogenic variants to justify the patient’s renal and ocular phenotypes. The identified c.465+1G>A was confirmed by studying the patient’s mRNA to result in exon skipping and early protein truncation, p.(Trp127CysfsTer8). Our study increases the number of patients and variants associated with FRA10AC1-related disorder and contributes to increasing our understanding of FRA10AC1 role in neurodevelopmental disorders. In addition, it reinforces kidney and ocular anomalies as part of this multisystem disorder.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"71 6","pages":"363-367"},"PeriodicalIF":2.5,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s10038-025-01447-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146029964","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}

引用次数: 0

JHG Young Scientist Award 2025 2025年JHG青年科学家奖。

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2026-01-20 DOI: 10.1038/s10038-026-01453-2

Toshihiro Tanaka

引用次数: 0

Meta-analyses of genome-wide association studies identify novel loci influencing Japanese white matter hyperintensities 全基因组关联研究的荟萃分析确定了影响日本白质高强度的新位点。

IF 2.3 3区生物学

Journal of Human Genetics Pub Date : 2026-01-20 DOI: 10.1038/s10038-026-01454-1

Yuya Asanomi, Risa Mitsumori, Akiko Yamakawa, Takashi Morizono, Daichi Shigemizu, Shumpei Niida, Takashi Sakurai, Kouichi Ozaki

{"title":"Meta-analyses of genome-wide association studies identify novel loci influencing Japanese white matter hyperintensities","authors":"Yuya Asanomi, Risa Mitsumori, Akiko Yamakawa, Takashi Morizono, Daichi Shigemizu, Shumpei Niida, Takashi Sakurai, Kouichi Ozaki","doi":"10.1038/s10038-026-01454-1","DOIUrl":"10.1038/s10038-026-01454-1","url":null,"abstract":"White matter hyperintensities (WMH) are common findings on brain magnetic resonance imaging (MRI) in older adults and are associated with an increased risk of dementia and stroke. Although large-scale European genome-wide association studies (GWAS) have identified more than 20 loci associated with WMH, the genetic architecture of WMH in Asian populations has not been fully elucidated. Here, we conducted a GWAS comprising 1001 Japanese individuals from the National Center for Geriatrics and Gerontology (NCGG) Biobank, followed by a meta-analysis with GWAS data from 9479 individuals in the Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD), identifying three novel loci significantly associated with WMH volume (P < 5 × 10−8). A subsequent trans-ethnic meta-analysis with UK Biobank data revealed twelve genome-wide significance loci, including one novel locus. Cis-expression quantitative trait locus (cis-eQTL) analyses using blood RNA-Seq data implicated 39 genes, especially showing downregulation of ACOX1 at a chromosome 17 locus. Protein QTL (pQTL) analyses using plasma proteomics data further demonstrated associations between these loci and increased levels of immune and inflammatory proteins. These findings provide new insights into the genetic architecture of WHH in the Japanese population and highlight immune and inflammatory pathways in the pathogenesis of age-related neurological diseases.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"71 7","pages":"397-403"},"PeriodicalIF":2.3,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s10038-026-01454-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003700","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}

引用次数: 0