Human Genetics最新文献

{"title":"The molecular landscape of hereditary ataxia: a single-center study.","authors":"Elisa Bregant, Elena Betto, Chiara Dal Secco, Jessica Zucco, Federica Baldan, Lorenzo Allegri, Incoronata Renata Lonigro, Flavio Faletra, Lorenzo Verriello, Giuseppe Damante, Catia Mio","doi":"10.1007/s00439-025-02744-y","DOIUrl":"https://doi.org/10.1007/s00439-025-02744-y","url":null,"abstract":"<p><p>Hereditary ataxia (HA) is a heterogeneous group of complex neurological disorders, which represent a diagnostic challenge due to their diverse phenotypes and genetic etiologies. Next-generation sequencing (NGS) has revolutionized the field of neurogenetics, improving the identification of ataxia-associated genes. Notwithstanding, repeat expansions analysis remains a cornerstone in the diagnostic workflow of these diseases. Here we describe the molecular characterization of a consecutive single-center series of 70 patients with genetically uncharacterized HA. Patients' samples were analyzed for known HA-associated repeat expansions as first tier and negative ones were analyzed by whole exome sequencing (WES) as second tier. Overall, we identified pathogenic/likely pathogenic variants in 40% (n = 28/70) and variants of unknown significance (VUS) in 20% (n = 14/70) of cases. In particular, 10 patients (14.3%, n = 10/70) presented pathogenic repeat expansions while 18 cases (30%, n = 18/60) harbored at least a single nucleotide variant (SNV) or a copy number variant (CNV) in HA or HSP-related genes. WES allowed assessing complex neurological diseases (i.e., leukodystrophies, cerebrotendinous xanthomatosis and atypical xeroderma pigmentosum), which are not usually referred as pure genetic ataxias. Our data suggests that the combined use of repeat expansion analysis and WES, coupled to detailed clinical phenotyping, is able to detect the molecular alteration underpinning ataxia in almost 50% cases, regardless of the hereditary pattern. Indeed, NGS-based tests are fundamental to acknowledge novel HA-associated genes useful to explain the remaining wide fraction of negative tests. Nowadays, this gap is problematic since these patients could not benefit from an etiological diagnosis of their disease that allows prognostic trajectories and prenatal/preimplantation diagnosis.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"144 5","pages":"545-557"},"PeriodicalIF":3.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12033174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144008770","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":"Letter to the editor.","authors":"Wouter H van der Valk, Winnie M C van den Boogaard, Esther Fousert, Heiko Locher","doi":"10.1007/s00439-025-02741-1","DOIUrl":"10.1007/s00439-025-02741-1","url":null,"abstract":"","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"591-593"},"PeriodicalIF":3.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763920","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":"Congenital enteropathy caused by ezrin deficiency.","authors":"Georg F Vogel, Katharina M C Klee, Arzu Meltem Demir, Dorota Garczarczyk-Asim, Michael W Hess, Lukas A Huber, Thomas Müller, Andreas R Janecke","doi":"10.1007/s00439-025-02738-w","DOIUrl":"10.1007/s00439-025-02738-w","url":null,"abstract":"<p><p>Ezrin, encoded by EZR, is a central module of epithelial polarity and links membrane proteins to the actin cytoskeleton directly or indirectly through scaffold proteins in the epithelium. Ezrin knockout mice fail to thrive and do not survive past weaning. We identified a homozygous EZR loss-of-function (LoF) variant, c.356dup, by exome sequencing in an infant with intractable diarrhea and failure to thrive, who died from septicemia at 5 months of age. The variant localized within a homozygous region of 13.2 Mb in the proband, is consistent with inheritance identical-by-descent from the consanguineous parents, and segregated with disease in the proband's family. EZR transcript analyses in a heterozygous carrier showed that the variant triggers nonsense-mediated mRNA decay. Homozygous EZR LoF variants have not been reported in public databases. In this study, we generated a Caco-2 EZR knockout cell line to investigate the role of ezrin in human intestinal epithelia. Our analyses used electron and immunofluorescence microscopy to assess structural changes in the knockout cells. We observed significant disorganization of the terminal web region, microvillus rarefaction and abnormal branching. Furthermore, the absence of ezrin resulted in the mislocalization of the ezrin-interacting scaffold protein Na+/H + exchanger regulatory factor-1. In conclusion, this represents the first documentation of complete ezrin deficiency in humans, highlighting the essential and non-redundant functions of the protein in maintaining intestinal physiology.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"505-514"},"PeriodicalIF":3.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12033192/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729989","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":"A latent outcome variable approach for Mendelian randomization using the stochastic expectation maximization algorithm.","authors":"Lamessa Dube Amente, Natalie T Mills, Thuc Duy Le, Elina Hyppönen, S Hong Lee","doi":"10.1007/s00439-025-02739-9","DOIUrl":"https://doi.org/10.1007/s00439-025-02739-9","url":null,"abstract":"<p><p>Mendelian randomization (MR) is a widely used tool to uncover causal relationships between exposures and outcomes. However, existing MR methods can suffer from inflated type I error rates and biased causal effects in the presence of invalid instruments. Our proposed method enhances MR analysis by augmenting latent phenotypes of the outcome, explicitly disentangling horizontal and vertical pleiotropy effects. This allows for explicit assessment of the exclusion restriction assumption and iteratively refines causal estimates through the expectation-maximization algorithm. This approach offers a unique and potentially more precise framework compared to existing MR methods. We rigorously evaluate our method against established MR approaches across diverse simulation scenarios, including balanced and directional pleiotropy, as well as violations of the Instrument Strength Independent of Direct Effect (InSIDE) assumption. Our findings consistently demonstrate superior performance of our method in terms of controlling type I error rates, bias, and robustness to genetic confounding, regardless of whether individual-level or summary data is used. Additionally, our method facilitates testing for directional horizontal pleiotropy and outperforms MR-Egger in this regard, while also effectively testing for violations of the InSIDE assumption. We apply our method to real data, demonstrating its effectiveness compared to traditional MR methods. This analysis reveals the causal effects of body mass index (BMI) on metabolic syndrome (MetS) and a composite MetS score calculated by the weighted sum of its component factors. While the causal relationship is consistent across most methods, our proposed method shows fewer violations of the exclusion restriction assumption, especially for MetS scores where horizontal pleiotropy persists and other methods suffer from inflation.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"144 5","pages":"559-574"},"PeriodicalIF":3.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12033120/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144005978","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":"Advancing chronic myeloid leukemia research with next-generation sequencing: potential benefits, limitations, and future clinical integration.","authors":"Henry Sutanto, Laras Pratiwi, Pradana Zaky Romadhon, Siprianus Ugroseno Yudho Bintoro","doi":"10.1007/s00439-025-02745-x","DOIUrl":"https://doi.org/10.1007/s00439-025-02745-x","url":null,"abstract":"<p><p>Next-generation sequencing (NGS) has emerged as a powerful tool for advancing research in chronic myeloid leukemia (CML) by providing a deeper understanding of its genetic complexity. Beyond detecting the hallmark BCR::ABL1 fusion gene, NGS has enabled the identification of additional mutations associated with disease progression, therapy resistance, and clonal evolution. NGS also facilitates the detection of rare BCR::ABL1 fusion variants and cryptic rearrangements, offering a more refined genetic characterization of the disease. Additionally, it enhances the study of minimal residual disease (MRD) and evolving resistance patterns, which are crucial for developing targeted therapeutic strategies. However, challenges such as data interpretation, standardization, and cost constraints continue to limit the widespread application of NGS in routine research and clinical settings. This review explores the contributions of NGS to CML research, highlighting its role in uncovering novel genetic alterations, tracking clonal evolution, and identifying potential therapeutic targets. As sequencing technologies evolve, NGS is expected to further shape the future of CML research, providing critical insights that may ultimately refine disease management strategies.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"144 5","pages":"481-503"},"PeriodicalIF":3.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143990819","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":"Decade-long application of preimplantation genetic testing for DMD/BMD: analysis of five clinical strategies and embryo recombination patterns.","authors":"Weili Wang, Jing Dai, Xiao Hu, Wenbin He, Yifan Gu, Zhenxing Wan, Yi Zhang, Keli Luo, Wen Li, Qianjun Zhang, Fei Gong, Guangxiu Lu, Liang Hu, Yue-Qiu Tan, Ge Lin, Juan Du","doi":"10.1007/s00439-025-02728-y","DOIUrl":"10.1007/s00439-025-02728-y","url":null,"abstract":"<p><p>This study aimed to find the most effective PGT-M strategy for Duchenne muscular dystrophy/Becker muscular dystrophy (DMD/BMD), and to reduce misdiagnosis caused by embryo recombination in DMD. A retrospective study was performed by analyzing 158 PGT-M cycles for DMD/BMD in Reproductive and Genetic Hospital of CITIC-Xiangya between 2009 and 2023. Patients' backgrounds were collected. The effectiveness and safety for five different PGT-M strategies (1-5), including mutation testing from cleavage or trophoblast ectoderm (TE) cells and additional linkage analysis post-TE cell amplification, were analyzed. The embryonic recombination events were assessed for these cycles. Mutation analysis showed that 62.4% of the 125 families had DMD deletions, 16.0% had duplications, and 21.6% had single nucleotide variants (SNVs). Among 125 families, 104 (83.2%) had previously affected fetus or offspring. The highest diagnosis rate (99.56%) was achieved with Strategy 5, which combined mutation testing with SNP-based linkage analysis in TE cells. This strategy 5 also demonstrated an advantage in cases with recombination near the mutation. An intragenic recombination rate of 5.5% was observed in embryos, predominantly in the hotspots (exons 45-55 and exons 3-9) of DMD deletion/duplication mutations. Prenatal diagnosis for 52 families and successful outcomes in all 85 healthy deliveries (live birth rate, 65.89%, 85/129) validated the accuracy and effectiveness of PGT-M. This study provides a highly effective PGT-M strategy (Strategy 5) for DMD/BMD by comparing five different strategies, with the diagnostic yield reaching 99.56%. The results underscore the significance of monitoring intragenic recombination in DMD, which is a frequent occurrence in DMD/BMD.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"405-416"},"PeriodicalIF":3.8,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448848","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":"Unilateral, bilateral symmetric or asymmetric isolated hearing loss in patients with heterozygous KITLG variants.","authors":"Margaux Serey-Gaut, Ralyath Balogoun, Laurence Jonard, Geneviève Lina-Granade, Renaud Touraine, Marjolaine Willems, Nicola Hepp, Nanna Dahl Rendtorff, Mette Bertelsen, Natalie Loundon, Vincent Couloigner, Isabelle Lemiere, Judite de Oliveira, Serge Romana, Camille Porteret, Pierre Blanc, Luke Mansard, Sandrine Marlin, Anne-Françoise Roux, Véronique Pingault","doi":"10.1007/s00439-025-02730-4","DOIUrl":"10.1007/s00439-025-02730-4","url":null,"abstract":"<p><p>KITLG pathogenic variants have been associated to three distinct clinical presentations with different combinations of hearing loss and/or pigmentation abnormalities. However, its involvement in isolated hearing loss has not been confirmed since its initial description in two families. Besides, KITLG is so far the only gene prevailingly involved in unilateral isolated hearing loss. We therefore conducted a retrospective study of patients with KITLG alterations in the French national Reference Network for Genetic Hearing Loss and one case was added through the Genematcher exchange platform. We describe a series of monoallelic KITLG deletions and variations in a cohort of 14 symptomatic patients from eight unrelated families. All patients presented with unilateral, bilateral symmetric or asymmetric sensorineural hearing loss. When not profound, hearing loss was predominant on low frequencies. Most KITLG alterations are likely to result in loss-of-function and aggregate in the extracellular region, disrupting the KIT-binding domain or its structure. Penetrance is not complete, and unspecific pigmentation alterations were observed in only three patients. The present study confirms KITLG involvement in isolated unilateral, bilateral symmetric or asymmetric hearing loss. This confirmation indicates that genetic testing can be relevant in early-onset, non-sudden, isolated unilateral hearing loss.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"433-441"},"PeriodicalIF":3.8,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364408","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":"Mendelian randomization analysis and molecular mechanism study of childhood asthma and obstructive sleep apnea.","authors":"Xinyu Wang, Lin Zhang, Hao Chen, Ting Tian, Lulu Wu, Yuping Huang, Qian Cao, Lili Zhuang, Guoping Zhou","doi":"10.1007/s00439-025-02734-0","DOIUrl":"10.1007/s00439-025-02734-0","url":null,"abstract":"<p><p>Childhood asthma is a common chronic respiratory disorder influenced by various factors, and obstructive sleep apnea (OSA) has emerged as a significant comorbidity. This study sought to investigate the underlying molecular mechanisms of the comorbidity between childhood asthma and OSA through Mendelian randomization (MR) analysis. Gene expression and genotype data were analyzed from public databases, and single nucleotide polymorphisms (SNPs) related to both diseases were identified. Our research findings unveiled 242 gene pairs associated with childhood asthma and 350 gene pairs related to OSA. Among them, the three hub genes, namely LRP3, BAK1, and CLIC4, exhibited significant expression alterations in both diseases. These hub genes participate in multiple signal transduction pathways and exhibit a remarkable correlation with the infiltration of immune cells, suggesting that they exert a vital role in modulating the immune microenvironment. Further analyses, encompassing gene set enrichment and transcriptional regulation, emphasized the complex interplay between these genes and non-coding RNAs as well as transcription factors. Our study results stressed the bidirectional relationship between childhood asthma and OSA and accentuated the significance of early identification and targeted intervention. This study identified potential therapeutic targets and laid a foundation for formulating treatment strategies aimed at improving the conditions of children with these interrelated diseases.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"443-461"},"PeriodicalIF":3.8,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143541785","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":"Human organoids for rapid validation of gene variants linked to cochlear malformations.","authors":"Mohammad Faraz Zafeer, Memoona Ramzan, Duygu Duman, Ahmet Mutlu, Serhat Seyhan, M Tayyar Kalcioglu, Suat Fitoz, Brooke A DeRosa, Shengru Guo, Derek M Dykxhoorn, Mustafa Tekin","doi":"10.1007/s00439-024-02723-9","DOIUrl":"10.1007/s00439-024-02723-9","url":null,"abstract":"<p><p>Developmental anomalies of the hearing organ, the cochlea, are diagnosed in approximately one-fourth of individuals with congenital. The majority of patients with cochlear malformations remain etiologically undiagnosed due to insufficient knowledge about underlying genes or the inability to make conclusive interpretations of identified genetic variants. We used exome sequencing for the genetic evaluation of hearing loss associated with cochlear malformations in three probands from unrelated families deafness. We subsequently generated monoclonal induced pluripotent stem cell (iPSC) lines, bearing patient-specific knockins and knockouts using CRISPR/Cas9 to assess pathogenicity of candidate variants. We detected FGF3 (p.Arg165Gly) and GREB1L (p.Cys186Arg), variants of uncertain significance in two recognized genes for deafness, and PBXIP1(p.Trp574*) in a candidate gene. Upon differentiation of iPSCs towards inner ear organoids, we observed developmental aberrations in knockout lines compared to their isogenic controls. Patient-specific single nucleotide variants (SNVs) showed similar abnormalities as the knockout lines, functionally supporting their causality in the observed phenotype. Therefore, we present human inner ear organoids as a potential tool to validate the pathogenicity of DNA variants associated with cochlear malformations.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"375-389"},"PeriodicalIF":3.8,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12003500/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142948000","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":"The genetic footprint of the European Roma diaspora: evidence from the Balkans to the Iberian Peninsula.","authors":"Giacomo Francesco Ena, Aaron Giménez, Annabel Carballo-Mesa, Petra Lišková, Marcos Araújo Castro E Silva, David Comas","doi":"10.1007/s00439-025-02735-z","DOIUrl":"10.1007/s00439-025-02735-z","url":null,"abstract":"<p><p>The Roma people have a complex demographic history shaped by their recent dispersal from a South Asian origin into Europe, accompanied by continuous population bottlenecks and gene flow. After settling in the Balkans around 1,000 years ago, the Roma gradually dispersed across Europe, and approximately 500 years ago, they established in the Iberian Peninsula what is now one of the largest Roma populations in Western Europe. Focusing specifically on the Iberian Roma, we conducted the most comprehensive genome-wide analysis of European Roma populations to date. Using allele frequency and haplotype-based methods, we analysed 181 individuals to investigate their genetic diversity, social dynamics, and migration histories at both continental and local scales. Our findings demonstrate significant gene flow from populations encountered during the Roma's dispersal and confirm their South Asian origins. We show that, between the 14th and 19th centuries, the Roma spread westward from the Balkans in various waves, with multiple admixture events. Furthermore, our findings refute previous hypotheses of a North African dispersal route into Iberia and genetic connections to Jewish populations. The Iberian Roma exhibit ten times greater genetic differentiation compared to non-Roma Iberians, indicating significant regional substructure. Additionally, we provide the first genetic evidence of assortative mating within Roma groups, highlighting distinct mating patterns and suggesting a gradual shift towards increased integration with non-Roma individuals. This study significantly enhances our understanding of how demographic history and complex genetic structure have shaped the genetic diversity of Roma populations, while also highlighting the influence of their evolving social dynamics.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"463-479"},"PeriodicalIF":3.8,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12003505/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143648425","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}