Human Genetics最新文献

{"title":"Genetic ancestry proportion influences risk of adverse events from tuberculosis treatment in Brazil.","authors":"Jacqueline A Piekos, Gustavo Amorim, Felipe Ridolfi, Marcelo Cordeiro-Santos, Afrânio L Kritski, Marina C Figueiredo, Bruno B Andrade, Adalberto R Santos, David W Haas, Timothy R Sterling, Valeria C Rolla, Digna R Velez Edwards","doi":"10.1007/s00439-025-02809-y","DOIUrl":"10.1007/s00439-025-02809-y","url":null,"abstract":"<p><p>Tuberculosis (TB) treatment is highly effective, but response to therapy varies by geography and population subgroups. We assessed differences in TB treatment response in a representative and heterogeneous Brazilian population. We estimated genetic ancestry according to major genetic ancestry groups (African, European, and Amerindian) in the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil cohort using ADMIXTURE software. RePORT-Brazil is an observational prospective cohort study of individuals with newly-diagnosed, culture-confirmed, pulmonary TB. Outcomes attributed to TB treatment included Grade 2 or higher adverse drug reaction (ADR), Grade 3 or higher ADR, hepatic ADR, and failure/recurrence. Genetic ancestry proportions were evaluated as predictors in univariate and multivariable logistic regression models for each outcome, and in stratified models for each genetic ancestry group. There were 930 pulmonary TB patients included in this study. In multivariable models we observed a decreased risk of Grade 2 + ADR when African ancestry proportion increased by 10% (Odds Ratio [OR] 0.41, 95% Confidence Interval [CI] 0.20-0.85) and an increased risk for Grade 2 + ADR with increasing European genetic ancestry (OR 2.33, 95% CI 1.14-4.76). In secondary analyses evaluating the interaction of HIV and genetic ancestry, we observed a statistically significant interaction between HIV and African genetic ancestry, but significantly decreased risk for Grade 2 + ADR with increasing African ancestry proportion. There were no associations with Amerindian genetic ancestry or for other treatment outcomes. In this Brazilian TB cohort, increased toxicity risk was associated with decreased African and increased European ancestry proportion.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":"10"},"PeriodicalIF":3.4,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12774987/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145911300","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":"Profiling structural variations of the α-globin gene cluster by the single molecule real-time sequencing: remarkable diversity of the spectrum with rare and novel variants identified in a large Chinese cohort.","authors":"Dan Wei, Zifeng Cheng, Wei Wei, Chunrong Gui, Juliang Liu, Hongfei Chen, Yunting Ma, XianWei Peng, Dan Yu, Yan Huang, Yinghui Lai, Baoheng Gui","doi":"10.1007/s00439-025-02801-6","DOIUrl":"10.1007/s00439-025-02801-6","url":null,"abstract":"<p><p>α-thalassemia is an inherited monogenic disorder that exhibits a notably high prevalence in the Guangxi region of China. Subjects in this study were recruited from the Second Affiliated Hospital of Guangxi Medical University between October 2021 and December 2024. Hematological phenotypes were evaluated, followed by structural variations profiling using SMRT sequencing. Novel structural variants were validated using multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing, while hematological phenotypic analysis was performed on the corresponding pedigrees. In this cohort of 1,430 subjects, 381 subjects (26.64%, 381/1430) exhibited structural variations in the α-globin gene cluster. Of the 381 subjects with α-globin structural variants, 355 were heterozygotes, 23 were compound heterozygotes, and 3 were homozygotes, collectively accounting for 407 alleles. SMRT analysis identified fourteen distinct structural variants, with the --SEA deletion representing the predominant variant at a frequency of 60.44% (246/407), followed by the -α3.7 (23.34%, 95/407) and -α4.2 (10.07%, 41/407) deletions. Furthermore, eleven rare variants were detected at an aggregate frequency of 6.14% (25/407), including --THAI, -α2.4, -α21.9, --11.1, HKαα, --120 (chr16:85493–205576 del), --35.2 (chr16:150825–186025 del), αααanti3.7, αααanti4.2, αααα3.7, and (αα)Fusion. Notably, two novel α0-thalassemia deletions (--120 and --35.2) associated with microcytic hypochromic anemia were identified, representing previously unreported rare deletions. The structural variation of the α-globin gene cluster is remarkably diverse. The novel variants identified in this study expand the variant spectrum in thalassemia. These findings provide support for thalassemia genetic counseling, diagnosis, and disease management. SMRT sequencing demonstrates superior capability in variant detection and significant potential for clinical diagnostic applications.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":"9"},"PeriodicalIF":3.4,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12769971/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145900435","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":"Genome-wide association study identifies novel and confirms established loci associated with serum lipids levels in Brazilians.","authors":"Larissa Siqueira Penna, Raphael Bruno Amemiya, Isabela Archanjo Nunez, Ágnis Iohana de Souza Grefenhagen, Vinicius Sousa Flores, Maria Vitoria Lima Oliveira, Liriel Almodobar, Jessica Honorato Mauer, Felipe Aristides Simão Neto, Ricardo di Lazzaro Filho, Guilherme Lopes Yamamoto","doi":"10.1007/s00439-025-02811-4","DOIUrl":"10.1007/s00439-025-02811-4","url":null,"abstract":"<p><p>Dyslipidemia is an important risk factor for cardiovascular diseases and can result from genetic and environmental influences. Most genome-wide association studies (GWAS) have been conducted in European populations, limiting our understanding of polymorphisms involved in lipid levels in admixed populations such as Brazilians. Therefore, this study aimed to identify genetic variants associated with lipid traits and develop polygenic risk scores (PRS) for dyslipidemia prediction in a large cohort of Brazilians. We performed GWAS of lipid phenotypes using 19,016 Brazilian individuals previously genotyped with SNP array and with available biochemical lipid measurements. After quality control and imputation, GWAS analyses were conducted separately for triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and non-HDL cholesterol (non-HDL-C). Trans-ancestry PRS were constructed using PRS-CSx. A set of 161 lead genome-wide significant SNPs were identified across lipid traits, including 62 previously reported in different populations, and many others representing potential novel associations for TC and TG. PRS models showed consistent associations with lipid levels, with increasing prevalence of elevated TC, LDL-C, non-HDL-C, and TG across higher PRS deciles. The area under the curve (AUC) values ranged from 0.62 to 0.66 across traits, with the highest performances for TC, non-HDL-C and TG. This study provides new insights into the genetic architecture of lipid traits in an admixed Brazilian population. Our findings underscore the relevance of conducting GWAS in diverse populations, support the use of PRS for risk stratification and prevention, and point to novel targets for drug development.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":"7"},"PeriodicalIF":3.4,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145900411","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":"Distinct regulatory elements of SLC6A14 expression contribute to modification of cystic fibrosis phenotypes.","authors":"Mohsen Esmaeili, Cheng Wang, Fan Lin, Naim Panjwani, Adele Chan, Gengming He, Katherine Keenan, Julie Avolio, Ann Harris, Johanna M Rommens, Lisa J Strug","doi":"10.1007/s00439-025-02800-7","DOIUrl":"10.1007/s00439-025-02800-7","url":null,"abstract":"<p><p>The SLC6A14 gene on chromosome X modifies disease presentation in individuals with cystic fibrosis (CF). Population studies have revealed distinct proximal and distal SNP clusters associated with gastrointestinal and lung phenotypes, respectively. Given the co-localization of cis-eQTLs within the corresponding associated chromosomal regions, where less SLC6A14 expression aligns with improved phenotypic outcomes, we sought to understand the SNP contributions to SLC6A14 expression regulation. Using reporter gene assays, we show that the proximal cluster, aligning with pancreas eQTLs, provides variation in promoter activity that is allele-dependent. The more expansive distal cluster, aligning with primary nasal cell eQTLs, was surveyed and found to harbour an enhancer feature that augmented expression in conjunction with the promoter in cells of lung origin. The rs4446858 SNP present within the enhancer aligns with the binding motif of the IRF1 transcription factor, where the alternate C allele was found to respond to direct addition of IRF1 or its increase following IFN-γ stimulation, resulting in increased SLC6A14 expression. Our data support a conclusion that SLC6A14 expression in airway tissue is regulated, in part, by immune-responsive genetic features, likely involving goblet cells. While our findings support previous model system studies indicating beneficial acute effects of SLC6A14 expression, they also highlight a distinction between immune-related responses and cumulative effects of long term disease reflected as lung function in individuals with CF. Our studies emphasize the challenges of elucidating complex genetic loci where there are multiple levels of regulatory influence with competing contributions.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":"8"},"PeriodicalIF":3.6,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12769681/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145905823","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":"Partially connected neural networks for complex trait prediction: application to human height.","authors":"Haoyi Weng, Li Jiang, Zhifeng Zheng, Kaichen Tang, Di Zhang, Wenting Zhao, Jie Song, Minxi Bi, Senwei Tang, Teng Li, Ruoyan Chen, Caixia Li, Gang Chen","doi":"10.1007/s00439-025-02794-2","DOIUrl":"10.1007/s00439-025-02794-2","url":null,"abstract":"<p><p>Polygenic risk scores (PRS) are fundamental tools for complex trait prediction, yet conventional methods often struggle to capture non-linear genetic interactions and ancestry-specific genetic architectures. Here, we propose a chromosome-aware, partially connected neural network (PCNN) that models localized genetic contributions and non-linear interactions across the genome. Through simulations with varying heritability levels and causal variant proportions, we demonstrate PCNN’s robust performance in capturing polygenic architectures. Applied to height prediction in 51,164 Han Chinese individuals using multi-ancestry genome-wide association studies summary statistics, PCNN achieves an R² = 0.2718 for males and 0.2603 for females, showing comparable or improved predictive accuracy relative to existing PRS methods such as Lassosum and PRScs. By structuring PRS inputs at the chromosome level, PCNN reduces input dimensionality and improves computational efficiency without compromising predictive performance. Our sensitivity analyses reveal the model’s ability to optimize non-linear relationships through LeakyReLU activation functions. This work establishes PCNN as an effective framework for polygenic trait prediction, particularly valuable for modeling population-specific genetic architectures and precision medicine applications.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":"4"},"PeriodicalIF":3.4,"publicationDate":"2025-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145846684","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":"Identification of DNA methylation based prognostic subtype and signature in epithelial ovarian cancer.","authors":"Jingjing Zhou, Yuxin Chen, Wei Liu, Chao Wang, Lei Liu, Wei Geng, Linqing Chai, Dong Yang, Hongji Dai, Haixin Li, Yanrui Zhao, Kexin Chen, Hong Zheng, Lian Li","doi":"10.1007/s00439-025-02808-z","DOIUrl":"10.1007/s00439-025-02808-z","url":null,"abstract":"<p><p>DNA methylation plays a crucial role in the development and progression of cancer and has been utilized for subtyping various tumors. This study focused on classifying epithelial ovarian cancer (EOC) based on DNA methylation and characterizing the subtypes through an integrated analysis of genomic, transcriptomic, and clinical data. We performed genome-wide DNA methylation profiling on 137 EOC tumor tissues using Infinium MethylationEPIC array and four methylation subtypes (MS1-MS4) were identified by non-negative matrix factorization (NMF) approach, showing significant differences in prognosis (P = 2.413 × 10⁻⁹). The MS1 group showed the best prognosis and the most favorable response to paclitaxel in combination with platinum-based chemotherapy. MS2 exhibited a gene expression pattern of relatively high immune cell infiltration and MS3 had a gene expression pattern associated with metabolic related pathway with a moderate prognosis. In contrast, MS4 had the poorest prognosis and was marked by the highest methylation levels among the four subtypes. A four-differential methylation position (DMP) signature was constructed for prognosis prediction and nomogram was also developed for enhancing clinical utility. Together, this study identified a novel molecular subtype for EOC, elucidating the heterogeneity of EOC from an epigenetic perspective and providing a new strategy for personalized treatment options for EOC patients.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":"6"},"PeriodicalIF":3.4,"publicationDate":"2025-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145846744","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":"Age estimation of single nucleotide polymorphisms associated with autoinflammatory diseases in anatolia: insights from ancient and modern DNA.","authors":"Damla Karadavut, Gulsah Merve Kilinc, Idil Yet","doi":"10.1007/s00439-025-02793-3","DOIUrl":"10.1007/s00439-025-02793-3","url":null,"abstract":"<p><p>Autoinflammatory diseases are immune system disorders that arise from abnormalities in the innate immune system. With the advent of genome sequencing, several distinct genetic loci associated with different types of autoinflammatory diseases have been identified. However, the evolutionary history of these variants, such as the age of the alleles, has not been fully explored in human populations. In this study, we focus on Anatolia, a region with a rich and dynamic prehistory, serving as a hub for human migration and genetic interactions. We explore the age of mutations associated with autoinflammatory diseases that are prevalent in present-day Anatolia, including Familial Mediterranean Fever, Tumor Necrosis Factor Receptor Associated Periodic Fever Syndrome, and Behçet’s Disease. We use RELATE and analyze genomic data from six low-to-medium depth of coverage (0.74–6.02X) ancient (1500 BCE − 7955 BCE) and 16 modern individuals from Anatolia to estimate the ages of 26 SNPs associated with these autoinflammatory disorders. Our results show that allele ages range from 981.452 to 74080.4 generations. We find that Behçet’s Disease is the earliest to have appeared in Anatolia, followed by Tumor Necrosis Factor Receptor Associated Periodic Fever Syndrome and Familial Mediterranean Fever. We had used both modern and ancient samples to improve the accuracy of our estimates. A MEFV variant that is modestly associated with Familial Mediterranean Fever (rs61732874) age range of 8050 to 17929.8 generations, suggests that the origin of Familial Mediterranean Fever disease in Anatolia may date back further than previously thought. This is the first time that Tumor necrosis factor receptor-associated periodic syndrome SNP (rs4149584) age was calculated as 3263.58 to 8160.29 generations. In summary, understanding the age of these alleles is crucial, as it provides valuable insights into the historical prevalence of mutations linked to diseases in Anatolia and their role in the genetic landscape of the region.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":"5"},"PeriodicalIF":3.4,"publicationDate":"2025-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145846696","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":"Novel biallelic LSS variants in autosomal recessive hypotrichosis simplex: insights from a multi-omics approach.","authors":"Xiaxia Liu, Kai Liu, Yuda Wei, Yongzhen Qi, Yangyang Luo, Tingli Chen, Xiaohua Ye, Junxu Lu, Yunjia Li, Liangqian Jiang, Juan Teng, Xingzhu Geng, Chengcheng Gai, Hongyan Xu, Hui Wang, Lin Li, Chunhai Gao, Xiangyu Zhao","doi":"10.1007/s00439-025-02802-5","DOIUrl":"10.1007/s00439-025-02802-5","url":null,"abstract":"<p><p>Hypotrichosis simplex is a rare form of non-syndromic hereditary alopecia characterized by childhood-onset diffuse and progressive scalp and body hair loss. Several genes have been identified as being associated with hypotrichosis simplex, including LPAR6, LIPH, DSG4, SNRPE, APCDD1, and LSS, among others. In this study, by sequencing peripheral blood DNA from probands, four pairs of novel biallelic variants of LSS (c.1335dupT; p.Thr446Tyrfs*10 and c.893-175G > A, c.1025 T > G; p.Ile342Ser and c.386C > A; p.Arg129Gln, c.1054G > A; p.Gly352Arg and c.1594G > C; p.Glu532Gln, c.385C > T; p.Arg129Trp and c.1303G > C; p.Arg435Cys) were identified in four Chinese families with autosomal recessive hypotrichosis simplex, among which a deep intronic pathogenic variant (c.893-175G > A) at a non-canonical splice site was identified by integrated analysis of whole genome sequencing and RNAseq. LSS encodes lanosterol synthase, a key enzyme that plays a critical role in steroid metabolism and is essential for hair follicle development. Molecular structural modeling also revealed significant adverse effects of the identified variants as well. The thickened epidermis, absence of hair follicles, and sebaceous gland hyperplasia were present by histopathological staining in the available tissue from the core family. The non-canonical pathogenic variant leads not only to abnormal mRNA splicing but also to decreased expression of LSS. Our results demonstrate the pathogenicity of LSS variants in causing hypotrichosis simplex and highlight the significance of combined application of multiple sequencing technologies for accurate disease diagnosis.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":"3"},"PeriodicalIF":3.4,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145818834","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":"Exploratory analysis of HLA SNPs associated with occult HBV infection: a multicenter case-control study in Chinese blood donors.","authors":"Lin Zhou, Ying Yan, Huimin Ji, Huizhen Sun, Zhuoqun Lu, Le Chang, Lunan Wang","doi":"10.1007/s00439-025-02805-2","DOIUrl":"10.1007/s00439-025-02805-2","url":null,"abstract":"<p><p>Occult hepatitis B virus infection (OBI), characterized by detectable HBV DNA but undetectable HBsAg, poses diagnostic and clinical challenges, with host genetic factors, particularly HLA-mediated immune regulation, remaining poorly understood. Through whole-exome sequencing of 147 participants (74 OBI cases, 73 chronic HBsAg + controls), we identified four HLA single nucleotide polymorphisms (SNPs) associated with low OBI susceptibility and proposed a dual immune mechanism: Class I SNPs impair cytotoxic responses, while Class II SNPs dysregulate humoral immunity. Anti-HBs titers and age modulated genetic risk penetrance, with high anti-HBs increasing OBI susceptibility regardless of genotype, and genetic effects attenuating in individuals > 50 years. Integrating HLA genetic markers with serological and baseline characteristics significantly improved OBI susceptibility prediction (AUC 0.93), highlighting the role of HLA-mediated immunity in OBI pathogenesis and the potential of genetic markers for risk stratification in HBV-exposed individuals. Our findings elucidate HLA-mediated immune mechanisms underlying OBI and demonstrate the value of genetic markers in predicting the likelihood of developing OBI or progressing to chronic HBsAg + status among HBV-exposed individuals.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":"1"},"PeriodicalIF":3.4,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145818801","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":"Whole-exome sequencing in children with dyslexia implicates rare variants in CLDN3 and ion channel genes.","authors":"Krzysztof Marianski, Joel B Talcott, John Stein, Anthony P Monaco, Simon E Fisher, Dorothy V M Bishop, Dianne F Newbury, Silvia Paracchini","doi":"10.1007/s00439-025-02796-0","DOIUrl":"10.1007/s00439-025-02796-0","url":null,"abstract":"<p><p>Dyslexia is a specific difficulty in learning to read that affects 5-10% of school-aged children and is strongly influenced by genetic factors. While previous studies have identified common genetic variants associated with dyslexia, the role of rare variants has only recently begun to emerge from pedigree studies and has yet to be systematically tested in larger cohorts. Here, we present a whole-exome sequencing (WES) study of 53 individuals with dyslexia, followed by an analysis in 38 cases with reading difficulties and 82 controls assessed with reading measures. Of the 22 genes that had high-impact variants filtered through stringent bioinformatic approaches in at least three dyslexia cases, five genes were validated in the follow-up analysis: CACNA1D, CACNA1G, CLDN3, CNGB1, and CP. Notably, a specific variant (7-73769649-G-A; c.C401T; p.P134L) in the CLDN3 gene was identified in six independent cases, showing a four-fold higher frequency compared to population reference datasets. CACNA1D and CACNA1G encode subunits of voltage-gated calcium channels expressed in neurons, and variants in both genes have been implicated in neurodevelopmental disorders such as autism spectrum disorder (ASD) and epilepsy. Segregation analyses in available family members were consistent with patterns of dominant inheritance with variable expressivity. In total, high-impact variants in the five genes of interest were found in 26% (N = 14) of individuals of the discovery cohort. Overall, our findings support the involvement of rare variants in developmental dyslexia and indicate that larger WES studies may uncover additional associated genes.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":"2"},"PeriodicalIF":3.6,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12738642/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145819029","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}