Human Genetics最新文献

{"title":"The natural history and genotype–phenotype correlations of TMPRSS3 hearing loss: an international, multi-center, cohort analysis","authors":"Brett M. Colbert, Cris Lanting, Molly Smeal, Susan Blanton, Derek M. Dykxhoorn, Pei-Ciao Tang, Richard L. Getchell, Hedwig Velde, Mirthe Fehrmann, Ryan Thorpe, Prem Chapagain, Heidy Elkhaligy, Hannie Kremer, Helger Yntema, Lonneke Haer-Wigman, Shelby Redfield, Tieqi Sun, Saskia Bruijn, Astrid Plomp, Thadé Goderie, Jiddeke van de Kamp, Rolien H. Free, Jolien Klein Wassink-Ruiter, Josine Widdershoven, Els Vanhoutte, Liselotte Rotteveel, Marjolein Kriek, Marieke van Dooren, Lies Hoefsloot, Heriette H. W. de Gier, Amanda Schaefer, Diana Kolbe, Hela Azaiez, Grace Rabie, Armal Aburayyan, Mariana Kawas, Moien Kanaan, Jourdan Holder, Shin-ichi Usami, Zhengyi Chen, Pu Dai, Jeffrey Holt, Rick Nelson, Byung Yoon Choi, Eliot Shearer, Richard J. H. Smith, Ronald Pennings, Xue Zhong Liu","doi":"10.1007/s00439-024-02648-3","DOIUrl":"https://doi.org/10.1007/s00439-024-02648-3","url":null,"abstract":"<p><i>TMPRSS3</i>-related hearing loss presents challenges in correlating genotypic variants with clinical phenotypes due to the small sample sizes of previous studies. We conducted a cross-sectional genomics study coupled with retrospective clinical phenotype analysis on 127 individuals. These individuals were from 16 academic medical centers across 6 countries. Key findings revealed 47 unique <i>TMPRSS3</i> variants with significant differences in hearing thresholds between those with missense variants versus those with loss-of-function genotypes. The hearing loss progression rate for the DFNB8 subtype was 0.3 dB/year. Post-cochlear implantation, an average word recognition score of 76% was observed. Of the 51 individuals with two missense variants, 10 had DFNB10 with profound hearing loss. These 10 all had at least one of 4 TMPRSS3 variants predicted by computational modeling to be damaging to TMPRSS3 structure and function. To our knowledge, this is the largest study of TMPRSS3 genotype–phenotype correlations. We find significant differences in hearing thresholds, hearing loss progression, and age of presentation, by TMPRSS3 genotype and protein domain affected. Most individuals with TMPRSS3 variants perform well on speech recognition tests after cochlear implant, however increased age at implant is associated with worse outcomes. These findings provide insight for genetic counseling and the on-going design of novel therapeutic approaches.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"2011 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140834410","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":"A novel network-based method identifies a cuproplasia-related pan-cancer gene signature to predict patient outcome","authors":"Vu Viet Hoang Pham, Toni Rose Jue, Jessica Lilian Bell, Fabio Luciani, Filip Michniewicz, Giuseppe Cirillo, Linda Vahdat, Chelsea Mayoh, Orazio Vittorio","doi":"10.1007/s00439-024-02673-2","DOIUrl":"https://doi.org/10.1007/s00439-024-02673-2","url":null,"abstract":"<p>Copper is a vital micronutrient involved in many biological processes and is an essential component of tumour cell growth and migration. Copper influences tumour growth through a process called cuproplasia, defined as abnormal copper-dependent cell-growth and proliferation. Copper-chelation therapy targeting this process has demonstrated efficacy in several clinical trials against cancer. While the molecular pathways associated with cuproplasia are partially known, genetic heterogeneity across different cancer types has limited the understanding of how cuproplasia impacts patient survival. Utilising RNA-sequencing data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) datasets, we generated gene regulatory networks to identify the critical cuproplasia-related genes across 23 different cancer types. From this, we identified a novel 8-gene cuproplasia-related gene signature associated with pan-cancer survival, and a 6-gene prognostic risk score model in low grade glioma. These findings highlight the use of gene regulatory networks to identify cuproplasia-related gene signatures that could be used to generate risk score models. This can potentially identify patients who could benefit from copper-chelation therapy and identifies novel targeted therapeutic strategies.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"28 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140629680","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":"Examination of the shared genetic architecture between multiple sclerosis and systemic lupus erythematosus facilitates discovery of novel lupus risk loci","authors":"Sophia Kerns, Katherine A. Owen, Dana Schwalbe, Amrie C. Grammer, Peter E. Lipsky","doi":"10.1007/s00439-024-02672-3","DOIUrl":"https://doi.org/10.1007/s00439-024-02672-3","url":null,"abstract":"<p>Systemic Lupus Erythematosus (SLE) is an autoimmune disease with heterogeneous manifestations, including neurological and psychiatric symptoms. Genetic association studies in SLE have been hampered by insufficient sample size and limited power compared to many other diseases. Multiple Sclerosis (MS) is a chronic relapsing autoimmune disease of the central nervous system (CNS) that also manifests neurological and immunological features. Here, we identify a method of leveraging large-scale genome wide association studies (GWAS) in MS to identify novel genetic risk loci in SLE. Statistical genetic comparison methods including linkage disequilibrium score regression (LDSC) and cross-phenotype association analysis (CPASSOC) to identify genetic overlap in disease pathophysiology, traditional 2-sample and novel PPI-based mendelian randomization to identify causal associations and Bayesian colocalization were applied to association studies conducted in MS to facilitate discovery in the smaller, more limited datasets available for SLE. Pathway analysis using SNP-to-gene mapping identified biological networks composed of molecular pathways with causal implications for CNS disease in SLE specifically, as well as pathways likely causal of both pathologies, providing key insights for therapeutic selection.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"143 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140600004","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":"VARista: a free web platform for streamlined whole-genome variant analysis across T2T, hg38, and hg19","authors":"Noam Hadar, Vadim Dolgin, Katya Oustinov, Yuval Yogev, Tomer Poleg, Amit Safran, Ofek Freund, Nadav Agam, Matan M. Jean, Regina Proskorovski-Ohayon, Ohad Wormser, Max Drabkin, Daniel Halperin, Marina Eskin-Schwartz, Ginat Narkis, Sufa Sued-Hendrickson, Ilana Aminov, Maya Gombosh, Sarit Aharoni, Ohad S. Birk","doi":"10.1007/s00439-024-02671-4","DOIUrl":"https://doi.org/10.1007/s00439-024-02671-4","url":null,"abstract":"<p>With the increasing importance of genomic data in understanding genetic diseases, there is an essential need for efficient and user-friendly tools that simplify variant analysis. Although multiple tools exist, many present barriers such as steep learning curves, limited reference genome compatibility, or costs. We developed VARista, a free web-based tool, to address these challenges and provide a streamlined solution for researchers, particularly those focusing on rare monogenic diseases. VARista offers a user-centric interface that eliminates much of the technical complexity typically associated with variant analysis. The tool directly supports VCF files generated using reference genomes hg19, hg38, and the emerging T2T, with seamless remapping capabilities between them. Features such as gene summaries and links, tissue and cell-specific gene expression data for both adults and fetuses, as well as automated PCR design and integration with tools such as SpliceAI and AlphaMissense, enable users to focus on the biology and the case itself. As we demonstrate, VARista proved effective in narrowing down potential disease-causing variants, prioritizing them effectively, and providing meaningful biological context, facilitating rapid decision-making. VARista stands out as a freely available and comprehensive tool that consolidates various aspects of variant analysis into a single platform that embraces the forefront of genomic advancements. Its design inherently supports a shift in focus from technicalities to critical thinking, thereby promoting better-informed decisions in genetic disease research. Given its unique capabilities and user-centric design, VARista has the potential to become an essential asset for the genomic research community. https://VARista.link</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"6 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140600192","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":"Loss-of-function variants affecting the STAGA complex component SUPT7L cause a developmental disorder with generalized lipodystrophy","authors":"Johannes Kopp, Leonard A. Koch, Hristiana Lyubenova, Oliver Küchler, Manuel Holtgrewe, Andranik Ivanov, Christele Dubourg, Erika Launay, Sebastian Brachs, Stefan Mundlos, Nadja Ehmke, Dominik Seelow, Mélanie Fradin, Uwe Kornak, Björn Fischer-Zirnsak","doi":"10.1007/s00439-024-02669-y","DOIUrl":"https://doi.org/10.1007/s00439-024-02669-y","url":null,"abstract":"<p>Generalized lipodystrophy is a feature of various hereditary disorders, often leading to a progeroid appearance. In the present study we identified a missense and a frameshift variant in a compound heterozygous state in <i>SUPT7L</i> in a boy with intrauterine growth retardation, generalized lipodystrophy, and additional progeroid features. <i>SUPT7L</i> encodes a component of the transcriptional coactivator complex STAGA. By transcriptome sequencing, we showed the predicted missense variant to cause aberrant splicing, leading to exon truncation and thereby to a complete absence of SUPT7L in dermal fibroblasts. In addition, we found altered expression of genes encoding DNA repair pathway components. This pathway was further investigated and an increased rate of DNA damage was detected in proband-derived fibroblasts and genome-edited HeLa cells. Finally, we performed transient overexpression of wildtype SUPT7L in both cellular systems, which normalizes the number of DNA damage events. Our findings suggest <i>SUPT7L</i> as a novel disease gene and underline the link between genome instability and progeroid phenotypes.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"22 3 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140600126","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":"Genotype-phenotype correlation in CLCN4-related developmental and epileptic encephalopathy","authors":"Ahmed N. Sahly, Juan Sierra-Marquez, Stefanie Bungert-Plümke, Arne Franzen, Lina Mougharbel, Saoussen Berrahmoune, Christelle Dassi, Chantal Poulin, Myriam Srour, Raul E. Guzman, Kenneth A. Myers","doi":"10.1007/s00439-024-02668-z","DOIUrl":"https://doi.org/10.1007/s00439-024-02668-z","url":null,"abstract":"<p><i>CLCN4</i>-related disorder is a rare X-linked neurodevelopmental condition with a pathogenic mechanism yet to be elucidated. <i>CLCN4</i> encodes the vesicular 2Cl⁻/H⁺ exchanger ClC-4, and <i>CLCN4</i> pathogenic variants frequently result in altered ClC-4 transport activity. The precise cellular and molecular function of ClC-4 remains unknown; however, together with ClC-3, ClC-4 is thought to have a role in the ion homeostasis of endosomes and intracellular trafficking. We reviewed our research database for patients with <i>CLCN4</i> variants and epilepsy, and performed thorough phenotyping. We examined the functional properties of the variants in mammalian cells using patch-clamp electrophysiology, protein biochemistry, and confocal fluorescence microscopy. Three male patients with developmental and epileptic encephalopathy were identified, with differing phenotypes. Patients #1 and #2 had normal growth parameters and normal-appearing brains on MRI, while patient #3 had microcephaly, microsomia, complete agenesis of the corpus callosum and cerebellar and brainstem hypoplasia. The p.(Gly342Arg) variant of patient #1 significantly impaired ClC-4’s heterodimerization capability with ClC-3 and suppressed anion currents. The p.(Ile549Leu) variant of patient #2 and p.(Asp89Asn) variant of patient #3 both shift the voltage dependency of transport activation by 20 mV to more hyperpolarizing potentials, relative to the wild-type, with p.(Asp89Asn) favouring higher transport activity. We concluded that p.(Gly342Arg) carried by patient #1 and the p.(Ile549Leu) expressed by patient #2 impair ClC-4 transport function, while the p.(Asp89Asn) variant results in a gain-of-transport function; all three variants result in epilepsy and global developmental impairment, but with differences in epilepsy presentation, growth parameters, and presence or absence of brain malformations.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"70 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140600125","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":"Phenotypic and genetic effect of carotid intima-media thickness on the risk of stroke","authors":"Wenqiang Zhang, Jingwei Zhu, Xuan Wu, Tianle Feng, Wei Liao, Xuan Li, Jianci Chen, Li Zhang, Chenghan Xiao, Huijie Cui, Chao Yang, Peijing Yan, Yutong Wang, Mingshuang Tang, Lin Chen, Yunjie Liu, Yanqiu Zou, Xueyao Wu, Ling Zhang, Chunxia Yang, Yuqin Yao, Jiayuan Li, Zhenmi Liu, Xia Jiang, Ben Zhang","doi":"10.1007/s00439-024-02666-1","DOIUrl":"https://doi.org/10.1007/s00439-024-02666-1","url":null,"abstract":"<p>While carotid intima-media thickness (cIMT) as a noninvasive surrogate measure of atherosclerosis is widely considered a risk factor for stroke, the intrinsic link underlying cIMT and stroke has not been fully understood. We aimed to evaluate the clinical value of cIMT in stroke through the investigation of phenotypic and genetic relationships between cIMT and stroke. We evaluated phenotypic associations using observational data from UK Biobank (<i>N</i> = 21,526). We then investigated genetic relationships leveraging genomic data conducted in predominantly European ancestry for cIMT (<i>N</i> = 45,185) and any stroke (AS, N_case/N_control=40,585/406,111). Observational analyses suggested an increased hazard of stroke per one standard deviation increase in cIMT (cIMT_max-AS: hazard ratio (HR) = 1.39, 95%CI = 1.09–1.79; cIMT_mean-AS: HR = 1.39, 95%CI = 1.09–1.78; cIMT_min-AS: HR = 1.32, 95%CI = 1.04–1.68). A positive global genetic correlation was observed (cIMT_max-AS: <span>({r}_{g})</span>=0.23, <i>P</i>=9.44 × 10⁻⁵; cIMT_mean-AS: <span>({r}_{g})</span>=0.21, <i>P</i>=3.00 × 10⁻⁴; cIMT_min-AS: <span>({r}_{g})</span>=0.16, <i>P</i>=6.30 × 10⁻³). This was further substantiated by five shared independent loci and 15 shared expression-trait associations. Mendelian randomization analyses suggested no causal effect of cIMT on stroke (cIMT_max-AS: odds ratio (OR)=1.12, 95%CI=0.97–1.28; cIMT_mean-AS: OR=1.09, 95%CI=0.93–1.26; cIMT_min-AS: OR=1.03, 95%CI = 0.90–1.17). A putative association was observed for genetically predicted stroke on cIMT (AS-cIMT_max: beta=0.07, 95%CI = 0.01–0.13; AS-cIMT_mean: beta=0.08, 95%CI = 0.01–0.15; AS-cIMT_min: beta = 0.08, 95%CI = 0.01–0.16) in the reverse direction MR, which attenuated to non-significant in sensitivity analysis. Our work does not find evidence supporting causal associations between cIMT and stroke. The pronounced cIMT-stroke association is intrinsic, and mostly attributed to shared genetic components. The clinical value of cIMT as a surrogate marker for stroke risk in the general population is likely limited.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"71 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140600079","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":"Prioritizing genomic variants pathogenicity via DNA, RNA, and protein-level features based on extreme gradient boosting","authors":"Maolin Ding, Ken Chen, Yuedong Yang, Huiying Zhao","doi":"10.1007/s00439-024-02667-0","DOIUrl":"https://doi.org/10.1007/s00439-024-02667-0","url":null,"abstract":"<p>Genetic diseases are mostly implicated with genetic variants, including missense, synonymous, non-sense, and copy number variants. These different kinds of variants are indicated to affect phenotypes in various ways from previous studies. It remains essential but challenging to understand the functional consequences of these genetic variants, especially the noncoding ones, due to the lack of corresponding annotations. While many computational methods have been proposed to identify the risk variants. Most of them have only curated DNA-level and protein-level annotations to predict the pathogenicity of the variants, and others have been restricted to missense variants exclusively. In this study, we have curated DNA-, RNA-, and protein-level features to discriminate disease-causing variants in both coding and noncoding regions, where the features of protein sequences and protein structures have been shown essential for analyzing missense variants in coding regions while the features related to RNA-splicing and RBP binding are significant for variants in noncoding regions and synonymous variants in coding regions. Through the integration of these features, we have formulated the Multi-level feature Genomic Variants Predictor (ML-GVP) using the gradient boosting tree. The method has been trained on more than 400,000 variants in the Sherloc-training set from the 6th critical assessment of genome interpretation with superior performance. The method is one of the two best-performing predictors on the blind test in the Sherloc assessment, and is further confirmed by another independent test dataset of de novo variants.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"20 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140600124","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":"Variant effect predictors: a systematic review and practical guide","authors":"Cristian Riccio, Max L. Jansen, Linlin Guo, Andreas Ziegler","doi":"10.1007/s00439-024-02670-5","DOIUrl":"https://doi.org/10.1007/s00439-024-02670-5","url":null,"abstract":"<p>Large-scale association analyses using whole-genome sequence data have become feasible, but understanding the functional impacts of these associations remains challenging. Although many tools are available to predict the functional impacts of genetic variants, it is unclear which tool should be used in practice. This work provides a practical guide to assist in selecting appropriate tools for variant annotation. We conducted a MEDLINE search up to November 10, 2023, and included tools that are applicable to a broad range of phenotypes, can be used locally, and have been recently updated. Tools were categorized based on the types of variants they accept and the functional impacts they predict. Sequence Ontology terms were used for standardization. We identified 118 databases and software packages, encompassing 36 variant types and 161 functional impacts. Combining only three tools, namely SnpEff, FAVOR, and SparkINFERNO, allows predicting 99 (61%) distinct functional impacts. Thirty-seven tools predict 89 functional impacts that are not supported by any other tool, while 75 tools predict pathogenicity and can be used within the ACMG/AMP guidelines in a clinical context. We launched a website allowing researchers to select tools based on desired variants and impacts. In summary, more than 100 tools are already available to predict approximately 160 functional impacts. About 60% of the functional impacts can be predicted by the combination of three tools. Unexpectedly, recent tools do not predict more impacts than older ones. Future research should allow predicting the functionality of so far unsupported variant types, such as gene fusions.</p><p>URL: https://cardio-care.shinyapps.io/VEP_Finder/.</p><p>Registration: OSF Registries on November 10, 2023, https://osf.io/s2gct.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"70 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140600120","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":"Functional categorization of gene regulatory variants that cause Mendelian conditions.","authors":"Y H Hank Cheng, Stephanie C Bohaczuk, Andrew B Stergachis","doi":"10.1007/s00439-023-02639-w","DOIUrl":"10.1007/s00439-023-02639-w","url":null,"abstract":"<p><p>Much of our current understanding of rare human diseases is driven by coding genetic variants. However, non-coding genetic variants play a pivotal role in numerous rare human diseases, resulting in diverse functional impacts ranging from altered gene regulation, splicing, and/or transcript stability. With the increasing use of genome sequencing in clinical practice, it is paramount to have a clear framework for understanding how non-coding genetic variants cause disease. To this end, we have synthesized the literature on hundreds of non-coding genetic variants that cause rare Mendelian conditions via the disruption of gene regulatory patterns and propose a functional classification system. Specifically, we have adapted the functional classification framework used for coding variants (i.e., loss-of-function, gain-of-function, and dominant-negative) to account for features unique to non-coding gene regulatory variants. We identify that non-coding gene regulatory variants can be split into three distinct categories by functional impact: (1) non-modular loss-of-expression (LOE) variants; (2) modular loss-of-expression (mLOE) variants; and (3) gain-of-ectopic-expression (GOE) variants. Whereas LOE variants have a direct corollary with coding loss-of-function variants, mLOE and GOE variants represent disease mechanisms that are largely unique to non-coding variants. These functional classifications aim to provide a unified terminology for categorizing the functional impact of non-coding variants that disrupt gene regulatory patterns in Mendelian conditions.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"559-605"},"PeriodicalIF":3.8,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11078748/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140021590","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}