Human molecular genetics最新文献_第2页

Viral vector-mediated SLC9A6 gene replacement reduces cerebellar motor and molecular abnormalities in the shaker rat model of Christianson syndrome. 病毒载体介导的SLC9A6基因替代减少Christianson综合征摇床大鼠模型的小脑运动和分子异常。

IF 3.2 2区生物学

Human molecular genetics Pub Date : 2026-03-23 DOI: 10.1093/hmg/ddag021

Collin J Anderson, Karla P Figueroa, Sharan Paul, Mandi Gandelman, Warunee Dansithong, Joseph A Katakowski, Daniel R Scoles, Stefan M Pulst

{"title":"Viral vector-mediated SLC9A6 gene replacement reduces cerebellar motor and molecular abnormalities in the shaker rat model of Christianson syndrome.","authors":"Collin J Anderson, Karla P Figueroa, Sharan Paul, Mandi Gandelman, Warunee Dansithong, Joseph A Katakowski, Daniel R Scoles, Stefan M Pulst","doi":"10.1093/hmg/ddag021","DOIUrl":"10.1093/hmg/ddag021","url":null,"abstract":"Background: Christianson syndrome is an x-linked recessive neurodevelopmental and neurodegenerative condition caused by mutations to the SLC9A6 gene encoding NHE6, a sodium-hydrogen exchanger critical for regulating endosomal pH. Using an adeno-associated viral (AAV) vector targeting Purkinje cells (PHP.eB-L7-Slc9a6-GFP), we recently performed functional complementation studies to demonstrate that mutation to the rat Slc9a6 gene causes a Christianson syndrome-relevant cerebellar phenotype in the shaker rat.Methods: We carried out a longitudinal study evaluating the impact of gene replacement targeting Purkinje cells on ataxia and tremor in the shaker rat. Further, in a smaller follow-up study, we tested administration of AAV9-CAG-hSLC9A6 to determine whether key molecular and motor findings could be replicated with a more clinically relevant viral construct. In both experimental cohorts, we performed molecular studies to evaluate expression of NHE6 and key cerebellar markers.Results: Administration of either of PHP.eB-L7-Slc9a6-GFP or AAV9-CAG-hSLC9A6 AAV vectors led to significant improvement in both the molecular and motor phenotypes. The abundance of each disease-relevant cerebellar proteins was strongly correlated to motor ataxia, but less so to tremor. Further, while ataxia and tremor were initially strongly correlated early in the disease progression, this relationship weakened over time.Conclusions: These findings impact future SLC9A6-targeted gene therapy efforts for Christianson syndrome and support gene replacement as a potentially viable therapeutic strategy. Common markers associated with cerebellar degeneration are much more strongly tied to ataxia than to tremor, indicating that ataxia may be more tied related to degenerative processes than tremor.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13050144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147618641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Comprehensive clinical and genetic profiling of Vietnamese pediatric hearing loss: a multi-region exome sequencing study. 越南儿童听力损失的综合临床和遗传分析：一项多区域外显子组测序研究。

IF 3.2 2区生物学

Human molecular genetics Pub Date : 2026-03-23 DOI: 10.1093/hmg/ddag027

Nguyen Cong Hoang, Duc-Minh Nguyen-Le, Huyen-Trang Thi Tran, Thanh Tra Nguyen, Manh Hung Nguyen, Dai-Phu Ngo, Giau Le, Hoang-Kim Van-Ho, Gia Huy Ha, Tran Trung Anh, Viet Hoang, Le Thi Huong Lan, Nguyen Minh Tuan, Dao Minh Nguyet, Bui Bang Giang, Le Dinh Thanh, Phu Hung Nguyen, Phuc-Loi Luu

{"title":"Comprehensive clinical and genetic profiling of Vietnamese pediatric hearing loss: a multi-region exome sequencing study.","authors":"Nguyen Cong Hoang, Duc-Minh Nguyen-Le, Huyen-Trang Thi Tran, Thanh Tra Nguyen, Manh Hung Nguyen, Dai-Phu Ngo, Giau Le, Hoang-Kim Van-Ho, Gia Huy Ha, Tran Trung Anh, Viet Hoang, Le Thi Huong Lan, Nguyen Minh Tuan, Dao Minh Nguyet, Bui Bang Giang, Le Dinh Thanh, Phu Hung Nguyen, Phuc-Loi Luu","doi":"10.1093/hmg/ddag027","DOIUrl":"https://doi.org/10.1093/hmg/ddag027","url":null,"abstract":"Congenital hearing loss (HL) in the Vietnamese population remains understudied despite its genetic diversity, limiting our understanding of its genetic etiology and hindering the development of effective, population-specific diagnostic strategies. In this descriptive cross-sectional whole-exome sequencing study, we enrolled 150 children with congenital non-syndromic HL (NSHL) from hospitals and hearing centers across Northern, Central, and Southern Vietnam to describe the genetic landscape of HL and provide new insights into rare and HL-associated variants. Clinical variant annotation was performed for 1589 deafness-associated genes, focusing on pathogenic, likely pathogenic, and variants of uncertain significance. Genetic factors strongly associated with NSHL accounted for 7.33% (11 of 150) of moderate-to-profound HL cases, involving both autosomal dominant and autosomal recessive inheritance patterns. Four variants across three genes were identified, namely GJB2:c.235del (p.L79CfsTer3), GJB2:c.109G > A (p.V37I), COCH:c.538C > T (p.R180Ter), and MYO6:c.2751dup (p.Q918TfsTer24). Two of these variants demonstrated a trend toward disease enrichment within the cohort, with the highest minor allele frequency (MAF) observed in GJB2:c.109G > A at 11%, followed by MYO6:c.2751dup at 2%. Although GJB2:c.235del showed a relatively high MAF of 1.3%, the observed minor alleles did not differ significantly from those in the East Asian and KHV control populations. These findings reveal distinct clinical and molecular profiles of congenital HL, providing essential knowledge for the development of targeted screening and diagnostic strategies tailored to the Vietnamese pediatric population.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147645095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Heterozygous loss-of-function variant in METTL5 is associated with intellectual disability. METTL5的杂合功能丧失变异与智力残疾有关。

IF 3.2 2区生物学

Human molecular genetics Pub Date : 2026-03-23 DOI: 10.1093/hmg/ddag018

Wenjun Tao, Yanqin Ying, Jiaju Sun, Yuxin Wu, Xinhui Jiang, Jun Zhang, Jun Zhou

{"title":"Heterozygous loss-of-function variant in METTL5 is associated with intellectual disability.","authors":"Wenjun Tao, Yanqin Ying, Jiaju Sun, Yuxin Wu, Xinhui Jiang, Jun Zhang, Jun Zhou","doi":"10.1093/hmg/ddag018","DOIUrl":"https://doi.org/10.1093/hmg/ddag018","url":null,"abstract":"Biallelic pathogenic variants in METTL5, which encodes an RNA methyltransferase involved in the m6A modification of 18S rRNA, have been reported as a rare etiology of autosomal recessive intellectual disability (ID). However, However, the clinical relevance of heterozygous variants in this gene remains unclear. In this study, we report a heterozygous frameshift variant located in exon 1 of the METTL5 gene identified in a father and son presenting with ID. Functional analyses demonstrated that this variant abolishes conserved domains, markedly reduces protein expression, and impairs 18S rRNA m6A modification, accompanied by decreased global protein synthesis. Proteomic profiling further revealed a downregulation of neuronal proteins involved in neuron projection, providing biological evidence supporting a potential role of METTL5 haploinsufficiency in neurodevelopmental processes. These observations suggest that heterozygous loss-of-function variants in METTL5, particularly those occurring early in the coding sequence, may be associated with an increased risk of neurodevelopmental disorders. Taken together, our study expands the mutational and phenotypic spectrum of METTL5-related disorders.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147503702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Genetic variation near ROBO1 is associated with craniofacial microsomia and related phenotypes in the Finnish population. 在芬兰人群中，ROBO1附近的遗传变异与颅面短小症和相关表型相关。

IF 3.2 2区生物学

Human molecular genetics Pub Date : 2026-03-23 DOI: 10.1093/hmg/ddag020

Laura Kaprio, Anu Kiukkonen, Emma Juuri, David P Rice, Hanna M Ollila, Satu Strausz

{"title":"Genetic variation near ROBO1 is associated with craniofacial microsomia and related phenotypes in the Finnish population.","authors":"Laura Kaprio, Anu Kiukkonen, Emma Juuri, David P Rice, Hanna M Ollila, Satu Strausz","doi":"10.1093/hmg/ddag020","DOIUrl":"10.1093/hmg/ddag020","url":null,"abstract":"Craniofacial microsomia (CFM) encompasses a phenotypic continuum of congenital anomalies ranging from isolated microtia to more complex manifestations within the oculo-auriculo-vertebral spectrum, including Goldenhar syndrome, reflecting abnormal development of first and second pharyngeal arch-derived structures. While several genetic susceptibility loci have been reported, population-based evidence in individuals of European ancestry remains limited. Using nationwide data from FinnGen in the Finnish founder population, we identified a genome-wide significant association at a conserved intergenic locus near ROBO1, extending previous findings to a European ancestry cohort. The lead variant, rs62256696, lies within a regulatory region active in human embryonic craniofacial tissues during early development and shows concordant association with previously reported ROBO1 signals from non-European populations. Genetic correlation analyses demonstrated strong shared genetic architecture between CFM and auditory developmental phenotypes, consistent with the defined phenotypic continuum. Together, these findings extend previous observations to a new population context and support a role for regulatory variation at the ROBO1 locus in early craniofacial morphogenesis and auditory system development underlying craniofacial and auditory malformations.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13064855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147645107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Single-cell RNA sequencing dissect the immunological network of immune checkpoint inhibitors-induced myocarditis. 单细胞RNA测序分析免疫检查点抑制剂诱导的心肌炎的免疫网络。

IF 3.2 2区生物学

Human molecular genetics Pub Date : 2026-03-23 DOI: 10.1093/hmg/ddag025

Chen Yan, Cong Ye, Kai-Xuan Wang, Xin-Ran Li, Zhi-Ting Jiang, Si-Jia Bian, Han Nie, Yu-Hua Zhu, Hong Du, Lan Luo

{"title":"Single-cell RNA sequencing dissect the immunological network of immune checkpoint inhibitors-induced myocarditis.","authors":"Chen Yan, Cong Ye, Kai-Xuan Wang, Xin-Ran Li, Zhi-Ting Jiang, Si-Jia Bian, Han Nie, Yu-Hua Zhu, Hong Du, Lan Luo","doi":"10.1093/hmg/ddag025","DOIUrl":"https://doi.org/10.1093/hmg/ddag025","url":null,"abstract":"Immune checkpoint inhibitors (ICIs) targeted PD-1/PD-L1 axis generate immune-related adverse events such as myocarditis, limiting their clinical application. Herein, we tried to explore the potential mechanism of ICIs-induced myocarditis. We performed single-cell RNA sequencing of heart tissues and peripheral blood mononuclear cells (PBMC) collected from mice with or without a relative low dose of PD-1/PD-L1 inhibitor (BMS-1) treatment. Compared with PBS treatment, BMS-1 treatment increased T, B, NK cells, and neutrophils but decreased macrophages in the heart. Four T cell subclusters in the heart were identified, including Treg, LEF1+CD4+ T, CCL5+CD8+ T, and STMN1+CD8+ T cells. The BMS-1-heart exhibited increased CCL5+CD8+ T cells depicted by elevated Nkg7 and Ccl5 gene expression compared with the PBS-heart. The number of macrophages declined but revealed inflammatory activity in the BMS-1-heart. Interestingly, CCR5, a receptor for CCL5 expressed in both CCR2- resident and CCR2+ recruit macrophages in the heart, was upregulated by the BMS-1 treatment. In addition, fibroblasts, not endothelial cells, showed an inflammatory activation state. Last, we identified increased CCL5+CD8+ T cells in the BMS-1-PBMC. Immunofluorescence staining also confirmed significantly elevated CCL5+CD8+ T cells in the BMS-1-heart than that of PBS-heart. BMS-1 seems to recruit circulating CCL5+CD8+ T cells to the heart, which further interact with CCR5+ macrophages, resulting in fibroblast activation. The CCL5/CCR5 axis and circulating CCL5+CD8+ T cells may be potential therapeutic/diagnostic strategies for ICIs-induced myocarditis.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147618438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 microbiome quantitative trait locus in SLC39A8 modulates disease severity in synucleinopathy-induced models of Parkinson's disease. SLC39A8中的微生物组数量性状位点调节突触核蛋白病诱导的帕金森病模型的疾病严重程度。

IF 3.2 2区生物学

Human molecular genetics Pub Date : 2026-03-23 DOI: 10.1093/hmg/ddag024

Julianne C Yang, Jamilla Situ, Ryan Troutman, Ruowei Zhu, Margaret Black, Heidi Buri, Arjun Gutta, Fengrui Tian, Allyson Kang, Ezinne Aja, Amber Zeng, Rochelle W Lai, Jia Tan, Fengting Liang, Caitlyn Brahim, Grace Murphy, Aaron Ahdoot, Chao Peng, Jonathan P Jacobs

{"title":"A microbiome quantitative trait locus in SLC39A8 modulates disease severity in synucleinopathy-induced models of Parkinson's disease.","authors":"Julianne C Yang, Jamilla Situ, Ryan Troutman, Ruowei Zhu, Margaret Black, Heidi Buri, Arjun Gutta, Fengrui Tian, Allyson Kang, Ezinne Aja, Amber Zeng, Rochelle W Lai, Jia Tan, Fengting Liang, Caitlyn Brahim, Grace Murphy, Aaron Ahdoot, Chao Peng, Jonathan P Jacobs","doi":"10.1093/hmg/ddag024","DOIUrl":"10.1093/hmg/ddag024","url":null,"abstract":"Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor deficits, dopaminergic neuron loss, and α-synuclein (α-syn) aggregation. While rare mutations underlie familial PD, around 85% of cases are idiopathic. Emerging evidence implicates common genetic variants and the gut microbiome in PD risk, but their interaction has not been studied. We previously demonstrated that the PD-protective SLC39A8 variant rs13107325 (human A391T, corresponding to A393T in mouse) is associated with microbial compositional shifts in humans and reshapes the microbiome in SLC39A8 A393T knock-in mice. Here, we test whether this SNP modifies PD phenotypes in two α-synucleinopathy mouse models. In the human α-synuclein overexpression model, A393T carrier mice show reduced motor deficits, consistent with a protective role. However, in the α-synuclein preformed fibril (PFF) injection model, A393T carriers exhibit worsened motor deficits, increased dopaminergic terminal loss, and enhanced α-synuclein pathology spread. SNP- and model-specific microbiome changes correlated with motor outcomes. These included enrichment of Lactobacillus and Lactobacillaceae HT002 genera in A393T carriers with α-synuclein overexpression, and enrichment of Erysipelatoclostridium in PFF-injected A393T carriers. These findings suggest that SLC39A8 A393T-induced microbiome alterations are associated with differential disease outcomes depending on context. Our results are consistent with a model in which susceptibility gene SNPs may influence PD progression via the gut microbiome, though direct causal effects remain to be tested.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13069889/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147645093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

A reanalysis of a genome-wide association study on breast cancer in Asian populations using the SG10K_Health reference panel for imputation: a multi-Centre case-control analysis. 使用SG10K_Health参考小组对亚洲人群乳腺癌全基因组关联研究的再分析：一项多中心病例对照分析

IF 3.2 2区生物学

Human molecular genetics Pub Date : 2026-03-23 DOI: 10.1093/hmg/ddag015

Xuling Chang, Shivaani Mariapun, Mengyu Li, Ling Wang, Peh Joo Ho, Alexis Jiaying Khng, Kenneth R Muir, Artitaya Lophatananon, Kristan J Aronson, Rachel A Murphy, Ava Kwong, Chun Hang Au, Sung-Won Kim, Sue K Park, Daniel O Stram, Anna H Wu, Soo-Hwang Teo, Cheng-Har Yip, Nur Aishah Mohd Tai, Esther M John, Allison W Kurian, Motoki Iwasaki, Taiki Yamaji, Ji-Yeob Choi, Daehee Kang, Xiao-Ou Shu, Wei Zheng, Mikael Hartman, Ern Yu Tan, Veronique Kiak-Mien Tan, Geok Hoon Lim, Manjeet K Bolla, Alison M Dunning, Joe Dennis, Qin Wang, Marc Naven, Douglas F Easton, Rajkumar S/O Dorajoo, Weang-Kee Ho, Jingmei Li

{"title":"A reanalysis of a genome-wide association study on breast cancer in Asian populations using the SG10K_Health reference panel for imputation: a multi-Centre case-control analysis.","authors":"Xuling Chang, Shivaani Mariapun, Mengyu Li, Ling Wang, Peh Joo Ho, Alexis Jiaying Khng, Kenneth R Muir, Artitaya Lophatananon, Kristan J Aronson, Rachel A Murphy, Ava Kwong, Chun Hang Au, Sung-Won Kim, Sue K Park, Daniel O Stram, Anna H Wu, Soo-Hwang Teo, Cheng-Har Yip, Nur Aishah Mohd Tai, Esther M John, Allison W Kurian, Motoki Iwasaki, Taiki Yamaji, Ji-Yeob Choi, Daehee Kang, Xiao-Ou Shu, Wei Zheng, Mikael Hartman, Ern Yu Tan, Veronique Kiak-Mien Tan, Geok Hoon Lim, Manjeet K Bolla, Alison M Dunning, Joe Dennis, Qin Wang, Marc Naven, Douglas F Easton, Rajkumar S/O Dorajoo, Weang-Kee Ho, Jingmei Li","doi":"10.1093/hmg/ddag015","DOIUrl":"10.1093/hmg/ddag015","url":null,"abstract":"Genome-wide association studies (GWAS) have identified numerous genetic variants linked to breast cancer risk, but most discoveries come from European populations, limiting their applicability to other populations. Here, we show that the choice of genotype imputation reference panel, an essential step for GWAS, affects variant detection in Asian populations. Using two large breast cancer datasets from the Breast Cancer Association Consortium (n = 38 954 Asian samples), we compared the 1000 Genomes (1KG) reference panel with SG10K_Health (SG10K), an Asian-specific panel. SG10K imputed more rare variants and achieved higher accuracy for rare alleles (MAF < 0.001), while 1KG performed better for common variants in some contexts. Differences in panel performance influenced association signals, including breast cancer candidate loci such as FGFR2, TOX3, and ESR1. Together, these findings support the use of population-specific imputation panels as a means to improve variant discovery in underrepresented populations.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13017919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147503677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Simultaneous detection of small and large variants enhances the diagnosis of rare diseases using full genome sequencing. 同时检测小变异和大变异增强了全基因组测序对罕见病的诊断。

IF 3.2 2区生物学

Human molecular genetics Pub Date : 2026-02-23 DOI: 10.1093/hmg/ddaf204

Meng-Ju Melody Tsai, Hsiao-Jung Kao, Chun-Yu Wei, Hsiao-Huei Chen, Yen-Yin Chou, Miao-Zi Hung, Hsueh-Wen Hsueh, Sung-Tsang Hsieh, Pi-Chuan Fan, Yi-Fang Tu, Ju-Li Lin, Hui-An Chen, Rai-Hseng Hsu, Yin-Hsiu Chien, Wuh-Liang Hwu, Pui-Yan Kwok, Ni-Chung Lee

{"title":"Simultaneous detection of small and large variants enhances the diagnosis of rare diseases using full genome sequencing.","authors":"Meng-Ju Melody Tsai, Hsiao-Jung Kao, Chun-Yu Wei, Hsiao-Huei Chen, Yen-Yin Chou, Miao-Zi Hung, Hsueh-Wen Hsueh, Sung-Tsang Hsieh, Pi-Chuan Fan, Yi-Fang Tu, Ju-Li Lin, Hui-An Chen, Rai-Hseng Hsu, Yin-Hsiu Chien, Wuh-Liang Hwu, Pui-Yan Kwok, Ni-Chung Lee","doi":"10.1093/hmg/ddaf204","DOIUrl":"10.1093/hmg/ddaf204","url":null,"abstract":"Despite advances in exome and genome sequencing, many patients with suspected genetic disorders remain undiagnosed due to limitations in detecting complex structural variants. This study aimed to evaluate the diagnostic yield and clinical utility of Full-Genome Analysis (FGA), an integrated approach that combines short-read whole-genome sequencing (WGS), 10x Genomics linked-read sequencing, and Bionano optical genome mapping (OGM). Twenty-nine patients with unclear or inconclusive genetic diagnoses after standard testing were analyzed using an in-house FGA pipeline capable of simultaneously detecting single nucleotide variants (SNVs), copy number variants (CNVs), and structural variants (SVs). FGA established molecular diagnoses in 12 of 29 patients (41.4%), identifying nine pathogenic SNVs, three CNVs, and two complex SVs. Two CNVs were missed by chromosomal microarray, and both SVs were undetectable by short-read WES or WGS. Representative cases demonstrated that integrating OGM and linked-read sequencing improved detection of compound heterozygous variants and cryptic rearrangements that conventional methods failed to resolve. FGA substantially improved the diagnostic yield in patients with unresolved genetic disorders after conventional testing. Its ability to comprehensively detect small and large genomic variants within a single workflow highlights its potential as a next-generation diagnostic platform for rare disease evaluation.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145970812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Genome-wide meta-analysis identifies genetic risk loci for mono- and polyneuropathies in 983 477 individuals. 全基因组荟萃分析确定了983 477例个体的单一和多发性神经病的遗传风险位点。

IF 3.2 2区生物学

Human molecular genetics Pub Date : 2026-02-23 DOI: 10.1093/hmg/ddaf200

Martin Broberg, Finn Gen, Eija Kalso, Hanna M Ollila

{"title":"Genome-wide meta-analysis identifies genetic risk loci for mono- and polyneuropathies in 983 477 individuals.","authors":"Martin Broberg, Finn Gen, Eija Kalso, Hanna M Ollila","doi":"10.1093/hmg/ddaf200","DOIUrl":"10.1093/hmg/ddaf200","url":null,"abstract":"Peripheral neuropathies are common neurological disorders affecting sensory, autonomic, and motor nerves, with an estimated prevalence exceeding 2% in the general population. Typical symptoms include numbness and distal limb muscle weakness, resulting from somatosensory nerve damage. Here, we investigate the genetic architecture of mono- and polyneuropathies and their relationships with comorbid traits using data from FinnGen and the UK Biobank. Our genome-wide association study (GWAS) and meta-analysis identified 48 genome-wide significant (P < 5 × 10-8) independent loci and 66 fine-mapped credible sets. These included associations with genes involved in neurotransmitter signaling (HTR3A), immune function (HLA-DQB1, BCL11A), extracellular matrix remodeling (COL11A1, ADAMTS17, LOXL4), axon guidance and neural development (DCC, ETV1, NEGR1), and carpal tunnel syndrome (DIRC3). Public variant association data across cohorts, genetic correlation, and Mendelian randomization analyses supported shared genetic links of neuropathies with sleep problems, chronic pain, and psychiatric disorders. Together, our results highlight a strong polygenic basis for neuropathies and further confirm their genetic comorbid relationships with sleep, pain, psychiatric, and autoimmune traits.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13036838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Reversible cystogenesis in juvenile primate ADPKD models: evidence from PKD1 heterozygous monkeys. 幼年灵长类动物ADPKD模型的可逆膀胱发生：来自PKD1杂合猴的证据。

IF 3.2 2区生物学

Human molecular genetics Pub Date : 2026-02-23 DOI: 10.1093/hmg/ddag011

Shoma Matsumoto, Toshifumi Morimura, Kenichi Kobayashi, Keiichi Tsuji, Masataka Nakaya, Tomoyuki Tsukiyama, Ikuo Kawamoto, Takahiro Nakagawa, Etsuko Morishige, Koji Fukuda, Teppei Iwakiri, Kazuhiko Nozaki, Akihiro Kawauchi, Susumu Kageyama, Shinji Kume, Saori Nishio, Yasushi Itoh, Masatsugu Ema

{"title":"Reversible cystogenesis in juvenile primate ADPKD models: evidence from PKD1 heterozygous monkeys.","authors":"Shoma Matsumoto, Toshifumi Morimura, Kenichi Kobayashi, Keiichi Tsuji, Masataka Nakaya, Tomoyuki Tsukiyama, Ikuo Kawamoto, Takahiro Nakagawa, Etsuko Morishige, Koji Fukuda, Teppei Iwakiri, Kazuhiko Nozaki, Akihiro Kawauchi, Susumu Kageyama, Shinji Kume, Saori Nishio, Yasushi Itoh, Masatsugu Ema","doi":"10.1093/hmg/ddag011","DOIUrl":"https://doi.org/10.1093/hmg/ddag011","url":null,"abstract":"Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder caused predominantly by heterozygous mutations in the PKD1 gene, leading to progressive renal cyst formation. While PKD1 mutant mouse models have provided mechanistic insights, PKD1 heterozygous mice fail to replicate the early cystogenesis observed in human patients. To address this gap, we conducted a longitudinal study using PKD1 heterozygous cynomolgus monkeys. Serial renal ultrasonography from birth to five years of age-corresponding to human childhood-revealed progressive cyst development. Remarkably, a subset of cysts, particularly smaller ones, exhibited spontaneous regression over time. This phenomenon was also observed in PKD1 mosaic monkeys harboring mixed variant patterns. In contrast, monkeys with biallelic PKD1 loss-of-function variants developed severe cystic disease, kidney enlargement, hepatic cysts, and elevated serum creatinine, resembling the clinical features of advanced ADPKD. These findings demonstrate that early renal cysts may possess intrinsic plasticity, challenging the conventional view of ADPKD as a relentlessly progressive disorder. Our results suggest that the early stages of cystogenesis represent a potential therapeutic window for intervention, in which cyst regression may be promoted. The PKD1 heterozygous monkey model thus provides a valuable platform for studying the developmental dynamics of ADPKD and for evaluating novel therapeutic approaches targeting early cystic changes.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 5","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147473502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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