Human Genetics最新文献

{"title":"Recessive variants in TWNK cause syndromic and non-syndromic post-synaptic auditory neuropathy through MtDNA replication defects.","authors":"Xue Gao, Ying Ma, Wei-Qian Wang, Guo-Jian Wang, Kun Yang, Jin-Cao Xu, Sha-Sha Huang, Xiang Wang, Li-Min Hu, Xi Wang, Qiu-Quan Wang, Zhen-Dong Wang, Ming-Yu Han, Pu Dai, Yong-Yi Yuan","doi":"10.1007/s00439-025-02774-6","DOIUrl":"10.1007/s00439-025-02774-6","url":null,"abstract":"<p><p>Recessive variants in TWNK cause syndromes arising from mitochondrial DNA (mtDNA) depletion. Hearing loss is the most prevalent manifestation in individuals with these disorders. However, the clinical and pathophysiological features have not been fully elucidated. In this study, we collected five cases of hearing loss carrying bi-allelic TWNK variants from three unrelated Chinese families and identified two cases with isolated auditory neuropathy (AN) and three cases segregating with Perrault syndrome, characterized by AN, global developmental delay, and ovarian dysgenesis in females. All patients with cochlear implantation (CI) show poor speech discrimination outcomes, suggesting that the defect involves post-synaptic sites. In the mouse inner ear, Twinkle was immunolocalized to inner phalangeal cells and spiral ganglion neurons. Additionally, the broad expression pattern of Twinkle was observed in the auditory cortex, which to some extent explains the poor rehabilitation outcomes following CI. At the cellular level, Twinkle is localized at the mtDNA membrane, and the p.(Arg609AlaTer6) variant prevents the protein from reaching the mtDNA while the p.(Arg65Trp) variant exhibits a similar localization to the wild type, indicating a second mechanism of action. RT-PCR results indicated that the canonical transcript was abundant in the inner ear, while the shorter transcript was more abundant in the brain. Our findings revealed that bi-allelic TWNK variants lead to AN, which can be either syndromic or non-syndromic, with the molecular pathogenesis involving defects in mtDNA replication at post-synaptic sites. Patients with TWNK-associated conditions are not ideal candidates for CI and gene therapy may offer a solution for hearingrehabilitation.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"929-947"},"PeriodicalIF":3.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145023167","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}

{"title":"Analysis of blood-based DNA methylation signatures of aging and disease progression in inflammatory bowel disease.","authors":"Trevor Doherty, Edel McDermott, Sarah Jane Delany, Hugh Mulcahy, Therese M Murphy","doi":"10.1007/s00439-025-02779-1","DOIUrl":"https://doi.org/10.1007/s00439-025-02779-1","url":null,"abstract":"<p><p>Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders influenced by environmental factors and characterised by a dysregulated immune response. DNA methylation (DNAm) a key epigenetic mechanism plays a role in the etiology of complex diseases like IBD. Epigenetic clocks which estimate biological aging through DNAm patterns have also been linked to various health states, including IBD. Previously, we profiled DNA methylation in peripheral blood from adult IBD patients and controls using the Illumina 450K microarray (n = 184). We now expand this dataset with 8-year clinical follow-up data, including disease progression and treatment response. Additionally, we generate second and third-generation epigenetic clock measures in this cohort to investigate if IBD patients exhibit epigenetic age acceleration compared to healthy controls. We identified one CpG site (cg03583111) significantly differentially methylated in IBD patients with long-term clinical recurrence (after the first year of study) compared to non-recurrence (no treatment escalation after 8 years). We assessed DNAm aging signatures in IBD patients versus controls, finding evidence of significant epigenetic age acceleration, as measured by three epigenetic clocks (GrimAge, GrimAge2, and DunedinPACE), in IBD patients compared to controls. These associations were replicated in two independent IBD cohorts: adult (GSE87648, n = 377) and paediatric (GSE112611, n = 238). Moreover, we observed higher age acceleration (GrimAge, U = 669, p = 0.003) and a faster pace of aging (DunedinPACE, t = 3.233, p = 0.002) in patients with active UC compared to inactive disease, but not for CD. These findings suggest that blood-based DNAm signatures could serve as biomarkers for detecting, monitoring, and classifying IBD.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185725","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}

{"title":"Genetic differences between diagnosed and undiagnosed Celiac disease: a population-based study.","authors":"Mohammad Sayeef Alam, Brooke N Wolford, Kristian Hveem, Knut E A Lundin, Sebo Withoff, Iris H Jonkers, Ludvig M Sollid, Rebecka Hjort, Eivind Ness-Jensen","doi":"10.1007/s00439-025-02778-2","DOIUrl":"https://doi.org/10.1007/s00439-025-02778-2","url":null,"abstract":"<p><p>A large proportion of individuals with celiac disease (CeD) remain undiagnosed, often presenting at an older age of onset or with non-classical symptoms compared to diagnosed cases. Such heterogeneity might be related to genetic factors. The aim was to utilize a CeD-screened adult population to compare the genetic variants in known and newly diagnosed cases. In the fourth wave of the population-based Trøndelag Health Study (HUNT4) 826 CeD and 51,516 non-CeD individuals were included. Medical registries identified 361 previously diagnosed cases, while screening identified 465 new cases. A validated polygenic risk score (PRS) was used to assess the genetic risk of CeD among the two case groups versus non-CeD individuals. Additional genetic variants not included in the PRS were also analyzed. The PRS distinguished cases from non-cases with high accuracy (AUROC: 85% for known cases, 83% for new cases). The genetic variation explained by the PRS was similar for known and new cases (17.1% versus 14.5%). The odds ratio for being in the highest genetic risk group (top 10%) was 22.7 (95% CI 14.1-36.4) for known cases and 18.6 (95% CI 12.4-27.9) for new cases versus the median group (40%-60%). Differences in effect size among specific genome-wide variants were observed but were not significantly associated with CeD. A validated PRS showed significant genetic difference between CeD cases and the general population, with similar association in both known and newly diagnosed cases. This suggests that genetic architectures of the two groups are comparable, implying that other non-genetic factors may drive CeD in adults.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185774","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}

{"title":"Investigation of GSDME results in the identification of the first pathogenic synonymous variants and genotype-phenotype correlations.","authors":"Joseph J Chin, W Daniel Walls, Kai Wang, Amanda M Odell, Diana L Kolbe, Kevin T A Booth, Hela Azaiez, Richard J H Smith","doi":"10.1007/s00439-025-02782-6","DOIUrl":"https://doi.org/10.1007/s00439-025-02782-6","url":null,"abstract":"<p><p>Despite advances in the genetic diagnosis of hearing loss, there remains room for improvement. One way to improve the genetic diagnostic rate is the proper assessment of synonymous variants that are often bioinformatically filtered out. We used GSDME as a model to demonstrate the importance of assessing synonymous variants. Variants in the gene GSDME (also known as DFNA5) are associated with autosomal dominant nonsyndromic hearing loss. The hearing loss is typically progressive and downsloping. All reported causative variants of GSDME-related hearing loss involve the skipping of exon 8, which results in the expression of a constitutively active, but truncated protein that induces apoptosis of cochlear hair cells. A retrospective search of previously tested patients identified 3 novel pathogenic synonymous GSDME variants. The functional impact of these variants was confirmed in vitro via a minigene splicing assay. We also observed variant-dependent differences in the levels of aberrant splicing, leading us to hypothesize that partial loss of splicing will result in a less severe hearing loss phenotype as compared to complete loss of splicing. Audiometric analysis found an association between complete loss of splicing and greater initial and/or more quickly progressing hearing loss as compared to partial loss of splicing. Over the course of the study, we also found limited correlation between in silico prediction and in vitro observed effects of a variant on splicing, indicating the need to cautiously apply in silico prediction tools in the context of genetic diagnosis.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185806","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}

{"title":"Correction: A genomic tale of inbreeding in western Mediterranean human populations.","authors":"Candela L Hernández, Luis J Sánchez-Martínez, Francisco C Ceballos, Jean M Dugoujon, Luisa Pereira, Rosario Calderón","doi":"10.1007/s00439-025-02773-7","DOIUrl":"https://doi.org/10.1007/s00439-025-02773-7","url":null,"abstract":"","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124399","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}

{"title":"BRCA-CN: a blockchain-based framework to support public variant databases sharing in multi-center community for diagnostic reference and China regulatory science.","authors":"Shoufang Qu, Rongzhi Liu, Shisen Li, Chuanfeng Huang, Yingqian Zhang, Xuan Gao, Pingping Dai, Chao Xu, Rutao Yang, Xuchao Li, Guojun Ouyang, Kang Shao, Xiaoyan Chang, Feng Mu, Meng Yang, Jie Huang","doi":"10.1007/s00439-025-02764-8","DOIUrl":"10.1007/s00439-025-02764-8","url":null,"abstract":"<p><p>High-quality, regulatory-grade databases for precise genetic variant interpretation are critically needed for Chinese populations, where existing fragmented databases impede clinical effectiveness evaluations. We developed BRCA-CN, a consortium blockchain-based governance framework specifically designed for BRCA gene variant interpretation in Chinese populations. Our framework compiled 66,485 variants from 6,031 samples across six Chinese laboratories. A 15-expert panel conducted systematic variant curation using unified interpretation standards based on ACMG/AMP guidelines. Smart contracts ensured data integrity and accountability throughout the consensus process. After deduplication, we established a comprehensive database of 950 unique variants (BRCA1: 365, BRCA2: 585), completing consensus reviews for 607 sites with 462 achieving definitive interpretations. Comparison with ClinVar revealed 83.6% concordance, with AI validation (PrimateAI, REVEL, EVE) confirming high interpretation accuracy. The blockchain framework successfully enabled secure cross-institutional collaboration while maintaining data sovereignty and regulatory compliance. BRCA-CN demonstrates the transformative potential of blockchain technology in genomic medicine, addressing critical challenges in data sharing, standardization, and regulatory oversight. This framework provides a robust foundation for clinical decision-making and establishes a replicable model for population-specific genomic databases. Access to the BRCA-CN portal, user guides, and test data is provided in the supplementary materials, available at: https://oxygen-chamber.mgi-tech.com/sdb2.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"877-898"},"PeriodicalIF":3.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144952117","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}

{"title":"Unraveling potential reporting bias in Mendelian randomization studies.","authors":"Chenyu Zhao, Keqiang Ma","doi":"10.1007/s00439-025-02759-5","DOIUrl":"10.1007/s00439-025-02759-5","url":null,"abstract":"","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"899-900"},"PeriodicalIF":3.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144484153","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}

{"title":"FBRSL1 regulates the expression of chromatin regulators BRPF1 and KAT6A.","authors":"Gina Kastens, Hanna Berger-Santangelo, Sarah Gerstner, Roser Ufartes, Michaela Mischak, Annette Borchers, Silke Pauli","doi":"10.1007/s00439-025-02760-y","DOIUrl":"10.1007/s00439-025-02760-y","url":null,"abstract":"<p><p>FBRSL1-associated syndrome is a rare congenital malformation and intellectual disability syndrome caused by heterozygous truncating variants in Fibrosin-Like 1 (FBRSL1). While FBRSL1 is known to be involved in embryonic development, its precise molecular function remains poorly understood. Therefore, the aim of this study was to elucidate the molecular function of FBRSL1, which is thought to be essential for developmental processes, and to investigate the effect of patient-derived truncating FBRSL1 variants. Using chromatin immunoprecipitation followed by sequencing (ChIP-Seq), we show that FBRSL1 regulates the expression of epigenetic regulators. We demonstrate that FBRSL1 associates with the transcription factor Yin Yang 1 (YY1) and binds upstream of Bromodomain And PHD Finger containing 1 (BRPF1) and Lysine Acetyltransferase 6 A (KAT6A), two epigenetic regulators involved in embryonic development and linked to neurodevelopmental disorders. Furthermore, quantitative real-time PCR analysis revealed that truncating FBRSL1 variants lead to downregulation of BRPF1 and KAT6A in blood and fibroblasts derived from patients with the FBRSL1-associated syndrome. Consistently, loss of Fbrsl1 function in Xenopus laevis embryos, which results in a range of developmental abnormalities, including craniofacial and brain malformations, also leads to defects in the brpf1 and kat6a expression pattern. In summary, our findings support a function of FBRSL1 in regulating key genes involved in global epigenetic processes and embryonic development. These results provide mechanistic insights how FBRSL1 dysfunction contributes to the pathogenesis of FBRSL1-associated syndrome.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"809-826"},"PeriodicalIF":3.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12449339/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144626073","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}

{"title":"Genomic and molecular evidence that the LncRNA DSP-AS1 modulates desmoplakin expression.","authors":"Luisa Foco, Marzia De Bortoli, Fabiola Del Greco M, Laura S Frommelt, Chiara Volani, Diana A Riekschnitz, Benedetta M Motta, Christian Fuchsberger, Thomas Delerue, Uwe Völker, Tianxiao Huan, Martin Gögele, Juliane Winkelmann, Marcus Dörr, Daniel Levy, Melanie Waldenberger, Alexander Teumer, Peter P Pramstaller, Alessandra Rossini, Cristian Pattaro","doi":"10.1007/s00439-025-02761-x","DOIUrl":"10.1007/s00439-025-02761-x","url":null,"abstract":"<p><p>Cardiac desmosomes are specialized cell junctions responsible for cardiomyocytes mechanical coupling. Mutation in desmosomal genes cause autosomal dominant and recessive familial arrhythmogenic cardiomyopathy. Motivated by evidence that Mendelian diseases share genetic architecture with common complex traits, we assessed whether common variants in any desmosomal gene were associated with cardiac conduction traits in the general population. We analysed data of N = 4342 Cooperative Health Research in South Tyrol (CHRIS) study participants. We tested associations between genotype imputed variants covering the five desmosomal genes Desmoplakin (DSP), junction plakoglobin (JUP), plakophilin 2 (PKP2), desmoglein 2 (DSG2), and desmocollin 2 (DSC2), and P-wave, PR, QRS, and QT electrocardiographic intervals, using linear mixed models. Functional annotation and interrogation of publicly available genome-wide association study resources implicated potential connection with antisense long non-coding RNAs (lncRNAs), DNA methylation sites, and complex traits. Causality was tested via two-sample Mendelian randomization (MR) analysis and validated with functional in vitro follow-up in human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs). DSP variant rs2744389 was associated with QRS (P = 3.5 × 10^-6), with replication in the Microisolates in South Tyrol (MICROS) study (n = 636; P = 0.010). Observing that rs2744389 was associated with DSP-AS1 antisense lncRNA but not with DSP expression in multiple Genotype-Tissue Expression (GTEx) v8 tissues, we conducted two-sample Mendelian randomization analyses that identified causal effects of DSP-AS1 on DSP expression (P = 6.33 × 10^-5; colocalization posterior probability = 0.91) and QRS (P = 0.015). In hiPSC-CMs, DSP-AS1 expression downregulation through a specific GapmerR matching sequence led to significant DSP upregulation at both mRNA and protein levels. The evidence that DSP-AS1 has a regulatory role on DSP opens the venue for further investigations on DSP-AS1's therapeutic potential for conditions caused by reduced desmoplakin production.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"843-860"},"PeriodicalIF":3.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12449342/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144742049","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}

{"title":"Characterizing the HLA region's genetic architecture through local heritability and correlation analyses across complex traits in diverse ancestries.","authors":"Menghan Wei, Yunjia Liu, Yunqi Huang, Ana Vazquez, Xing Zhao, Miaoxin Li, Pak-Chung Sham, Hongsheng Gui, Qiang Wang","doi":"10.1007/s00439-025-02763-9","DOIUrl":"10.1007/s00439-025-02763-9","url":null,"abstract":"<p><p>The human leukocyte antigen (HLA) region is a critical genetic locus associated with diverse complex traits, yet its intricate genetic architecture poses significant challenges to elucidation. Leveraging recent advances in regional heritability estimation and extensive datasets from the Million Veteran Program (MVP), we conducted a comprehensive investigation of the HLA region's genetic architecture. This involved heritability estimation and genetic correlation analyses within the HLA region across European Americans (EAs) and African Americans (AAs). Our analyses demonstrated that in EAs, the HLA region exhibited significantly greater local heritability than other genomic regions of comparable length for lipid metabolic traits (triglycerides [TG], total cholesterol [TC], high-density lipoprotein [HDL], low-density lipoprotein [LDL]), anthropometric measures (body mass index [BMI]), and suicide-related traits (suicidal ideation without suicide attempts [IDE] and suicidal thoughts and behaviors [SITB]) (false discovery rate [FDR]-adjusted empirical p-values < 0.05). Notably, this enrichment was not observed in AAs. Genetic correlation analyses revealed disparities between local HLA and genome-wide findings. EAs exhibited 16 significant local HLA correlations and 32 genome-wide correlations. Conversely, AAs displayed more significant local genetic correlations within the HLA region (14 pairs) than genome-wide (3 pairs), with two pairs (IDE-SITB, LDL-TC) concordantly significant. These findings underscore the HLA region's substantial contribution to the variance of these lipid metabolic traits, BMI, and suicide-related traits. Further investigation into the genetic mechanisms by which HLA-mediated pathways influence these phenotypes is crucial for elucidating the complex role of this region, particularly concerning lipid metabolism and suicidal behaviors.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"827-841"},"PeriodicalIF":3.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144649394","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}