Human Genetics最新文献

{"title":"Histone H3K36 methyltransferases NSD1 and SETD2 are required for brain development.","authors":"Bo Chen, Chenyang Zhang, Huanwen Rui, Dan Shen, Zhuxi Huang, Weijun Feng","doi":"10.1007/s00439-025-02740-2","DOIUrl":"https://doi.org/10.1007/s00439-025-02740-2","url":null,"abstract":"<p><p>Genetic variants in two major histone H3K36 methyltransferases, NSD1 and SETD2, have been identified in patients with neurodevelopmental disorders. We examined the genetic nature of these disease-relevant variants and studied genotype-phenotype correlations using publicly available patient cohorts. To further investigate roles of Nsd1 and Setd2 in brain development, we generated mouse models with conditional knockout of Nsd1 and Setd2 in neuroepithelial cells using the Sox1-cre. Our results showed that conditional Nsd1 knockout mice were viable but exhibited reduced brain size and thinning of neocortex, while Setd2 knockout led to neonatal death with intracerebral hemorrhage and vascular abnormalities. Together, our study demonstrates new roles of Nsd1 and Setd2 in brain development.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811394","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":"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":"https://doi.org/10.1007/s00439-025-02741-1","url":null,"abstract":"","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-04-02","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":"Accelerating genetic diagnostics in retinitis pigmentosa: implementation of a semi-automated bespoke cohort analysis workflow for Hong Kong Genome Project.","authors":"Dingge Ying, Jamie Sui Lam Kwok, Annie Tsz Wai Chu, Wei Ma, Helen Ying Fung Tam, Dicky Or, Shirley Pik Ying Hue, Qing Li, Christopher Kai Shun Leung, Brian Hon Yin Chung","doi":"10.1007/s00439-025-02737-x","DOIUrl":"https://doi.org/10.1007/s00439-025-02737-x","url":null,"abstract":"<p><p>The study aims to enhance the efficiency of the genetic variant curation process at the Hong Kong Genome Institute by developing a Semi-Automated Bespoke Cohort Analysis Workflow (S-BCAW) for patients with, or suspected to have, retinitis pigmentosa (RP) in the Hong Kong Genome Project (HKGP), leveraging advances in next-generation sequencing (NGS). A comparative analysis involving 79 RP patients was conducted using both the conventional manual workflow and the novel S-BCAW, which integrates initial filtering and variant classification based on ACMG guidelines, followed by detailed manual review. The diagnostic yields from both methods were identical, but the bespoke workflow reduced analysis time by approximately 60% (1.5 h/sample). This efficiency increase resulted from automated application of ACMG rules and systematic aggregation of supportive data, including disease-specific information. The study reports 25 positive cases with a diagnostic yield of 32%, including three novel variants. The S-BCAW significantly improves efficiency, helping to end the diagnostic odyssey for patients in the HKGP. This approach facilitates rapid assessment of variant pathogenicity, enhancing the feasibility and timeliness of NGS technology for clinical applications, especially in urgent scenarios.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143752362","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":"https://doi.org/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":""},"PeriodicalIF":3.8,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"https://doi.org/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":""},"PeriodicalIF":3.8,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"https://doi.org/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":""},"PeriodicalIF":3.8,"publicationDate":"2025-03-03","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":"QAFI: a novel method for quantitative estimation of missense variant impact using protein-specific predictors and ensemble learning.","authors":"Selen Ozkan, Natàlia Padilla, Xavier de la Cruz","doi":"10.1007/s00439-024-02692-z","DOIUrl":"10.1007/s00439-024-02692-z","url":null,"abstract":"<p><p>Next-generation sequencing (NGS) has revolutionized genetic diagnostics, yet its application in precision medicine remains incomplete, despite significant advances in computational tools for variant annotation. Many variants remain unannotated, and existing tools often fail to accurately predict the range of impacts that variants have on protein function. This limitation restricts their utility in relevant applications such as predicting disease severity and onset age. In response to these challenges, a new generation of computational models is emerging, aimed at producing quantitative predictions of genetic variant impacts. However, the field is still in its early stages, and several issues need to be addressed, including improved performance and better interpretability. This study introduces QAFI, a novel methodology that integrates protein-specific regression models within an ensemble learning framework, utilizing conservation-based and structure-related features derived from AlphaFold models. Our findings indicate that QAFI significantly enhances the accuracy of quantitative predictions across various proteins. The approach has been rigorously validated through its application in the CAGI6 contest, focusing on ARSA protein variants, and further tested on a comprehensive set of clinically labeled variants, demonstrating its generalizability and robust predictive power. The straightforward nature of our models may also contribute to better interpretability of the results.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"191-208"},"PeriodicalIF":3.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141758427","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":"Assessing predictions on fitness effects of missense variants in HMBS in CAGI6.","authors":"Jing Zhang, Lisa Kinch, Panagiotis Katsonis, Olivier Lichtarge, Milind Jagota, Yun S Song, Yuanfei Sun, Yang Shen, Nurdan Kuru, Onur Dereli, Ogun Adebali, Muttaqi Ahmad Alladin, Debnath Pal, Emidio Capriotti, Maria Paola Turina, Castrense Savojardo, Pier Luigi Martelli, Giulia Babbi, Rita Casadio, Fabrizio Pucci, Marianne Rooman, Gabriel Cia, Matsvei Tsishyn, Alexey Strokach, Zhiqiang Hu, Warren van Loggerenberg, Frederick P Roth, Predrag Radivojac, Steven E Brenner, Qian Cong, Nick V Grishin","doi":"10.1007/s00439-024-02680-3","DOIUrl":"10.1007/s00439-024-02680-3","url":null,"abstract":"<p><p>This paper presents an evaluation of predictions submitted for the \"HMBS\" challenge, a component of the sixth round of the Critical Assessment of Genome Interpretation held in 2021. The challenge required participants to predict the effects of missense variants of the human HMBS gene on yeast growth. The HMBS enzyme, critical for the biosynthesis of heme in eukaryotic cells, is highly conserved among eukaryotes. Despite the application of a variety of algorithms and methods, the performance of predictors was relatively similar, with Kendall's tau correlation coefficients between predictions and experimental scores around 0.3 for a majority of submissions. Notably, the median correlation (≥ 0.34) observed among these predictors, especially the top predictions from different groups, was greater than the correlation observed between their predictions and the actual experimental results. Most predictors were moderately successful in distinguishing between deleterious and benign variants, as evidenced by an area under the receiver operating characteristic (ROC) curve (AUC) of approximately 0.7 respectively. Compared with the recent two rounds of CAGI competitions, we noticed more predictors outperformed the baseline predictor, which is solely based on the amino acid frequencies. Nevertheless, the overall accuracy of predictions is still far short of positive control, which is derived from experimental scores, indicating the necessity for considerable improvements in the field. The most inaccurately predicted variants in this round were associated with the insertion loop, which is absent in many orthologs, suggesting the predictors still heavily rely on the information from multiple sequence alignment.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"173-189"},"PeriodicalIF":3.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897332","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":"CAGI6 ID panel challenge: assessment of phenotype and variant predictions in 415 children with neurodevelopmental disorders (NDDs).","authors":"Maria Cristina Aspromonte, Alessio Del Conte, Shaowen Zhu, Wuwei Tan, Yang Shen, Yexian Zhang, Qi Li, Maggie Haitian Wang, Giulia Babbi, Samuele Bovo, Pier Luigi Martelli, Rita Casadio, Azza Althagafi, Sumyyah Toonsi, Maxat Kulmanov, Robert Hoehndorf, Panagiotis Katsonis, Amanda Williams, Olivier Lichtarge, Su Xian, Wesley Surento, Vikas Pejaver, Sean D Mooney, Uma Sunderam, Rajgopal Srinivasan, Alessandra Murgia, Damiano Piovesan, Silvio C E Tosatto, Emanuela Leonardi","doi":"10.1007/s00439-024-02722-w","DOIUrl":"10.1007/s00439-024-02722-w","url":null,"abstract":"<p><p>The Genetics of Neurodevelopmental Disorders Lab in Padua provided a new intellectual disability (ID) Panel challenge for computational methods to predict patient phenotypes and their causal variants in the context of the Critical Assessment of the Genome Interpretation, 6th edition (CAGI6). Eight research teams submitted a total of 30 models to predict phenotypes based on the sequences of 74 genes (VCF format) in 415 pediatric patients affected by Neurodevelopmental Disorders (NDDs). NDDs are clinically and genetically heterogeneous conditions, with onset in infant age. Here, we assess the ability and accuracy of computational methods to predict comorbid phenotypes based on clinical features described in each patient and their causal variants. We also evaluated predictions for possible genetic causes in patients without a clear genetic diagnosis. Like the previous ID Panel challenge in CAGI5, seven clinical features (ID, ASD, ataxia, epilepsy, microcephaly, macrocephaly, hypotonia), and variants (Pathogenic/Likely Pathogenic, Variants of Uncertain Significance and Risk Factors) were provided. The phenotypic traits and variant data of 150 patients from the CAGI5 ID Panel Challenge were provided as training set for predictors. The CAGI6 challenge confirms CAGI5 results that predicting phenotypes from gene panel data is highly challenging, with AUC values close to random, and no method able to predict relevant variants with both high accuracy and precision. However, a significant improvement is noted for the best method, with recall increasing from 66% to 82%. Several groups also successfully predicted difficult-to-detect variants, emphasizing the importance of variants initially excluded by the Padua NDD Lab.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"227-242"},"PeriodicalIF":3.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142947999","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":"Assessing the predicted impact of single amino acid substitutions in MAPK proteins for CAGI6 challenges.","authors":"Paola Turina, Maria Petrosino, Carlos A Enriquez Sandoval, Leonore Novak, Alessandra Pasquo, Emil Alexov, Muttaqi Ahmad Alladin, David B Ascher, Giulia Babbi, Constantina Bakolitsa, Rita Casadio, Jianlin Cheng, Piero Fariselli, Lukas Folkman, Akash Kamandula, Panagiotis Katsonis, Minghui Li, Dong Li, Olivier Lichtarge, Sajid Mahmud, Pier Luigi Martelli, Debnath Pal, Shailesh Kumar Panday, Douglas E V Pires, Stephanie Portelli, Fabrizio Pucci, Carlos H M Rodrigues, Marianne Rooman, Castrense Savojardo, Martin Schwersensky, Yang Shen, Alexey V Strokach, Yuanfei Sun, Junwoo Woo, Predrag Radivojac, Steven E Brenner, Roberta Chiaraluce, Valerio Consalvi, Emidio Capriotti","doi":"10.1007/s00439-024-02724-8","DOIUrl":"10.1007/s00439-024-02724-8","url":null,"abstract":"<p><p>New thermodynamic and functional studies have been recently conducted to evaluate the impact of amino acid substitutions on the Mitogen Activated Protein Kinases 1 and 3 (MAPK1/3). The Critical Assessment of Genome Interpretation (CAGI) data provider, at Sapienza University of Rome, measured the unfolding free energy and the enzymatic activity of a set of variants (MAPK challenge dataset). Thermodynamic measurements for the denaturant-induced equilibrium unfolding of the phosphorylated and unphosphorylated forms of the MAPKs were obtained by monitoring the far-UV circular dichroism and intrinsic fluorescence changes as a function of denaturant concentration. These values have been used to calculate the change in unfolding free energy between the variant and wild-type proteins at zero concentration of denaturant ( <math><mrow><mi>Δ</mi> <mi>Δ</mi> <msup><mi>G</mi> <mrow><msub><mtext>H</mtext> <mn>2</mn></msub> <mtext>O</mtext></mrow> </msup> </mrow> </math> ). The enzymatic activity of the phosphorylated MAPKs variants was also measured using Chelation-Enhanced Fluorescence to monitor the phosphorylation of a peptide substrate. The MAPK challenge dataset, composed of a total of 23 single amino acid substitutions (11 and 12 for MAPK1 and MAPK3, respectively), was used to assess the effectiveness of the computational methods in predicting the <math><mrow><mi>Δ</mi> <mi>Δ</mi> <msup><mi>G</mi> <mrow><msub><mtext>H</mtext> <mn>2</mn></msub> <mtext>O</mtext></mrow> </msup> </mrow> </math> values, associated with the variants, and categorize them as destabilizing and not destabilizing. The data on the enzymatic activity of the MAPKs mutants were used to assess the performance of the methods for predicting the functional impact of the variants. For the sixth edition of CAGI, thirteen independent research groups from four continents (Asia, Australia, Europe and North America) submitted > 80 sets of predictions, obtained from different approaches. In this manuscript, we summarized the results of our assessment to highlight the possible limitations of the available algorithms.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"265-280"},"PeriodicalIF":3.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11975483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457846","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}