Human Genetics最新文献

{"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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}

{"title":"Five years of experience in the Epigenetics and Chromatin Clinic: what have we learned and where do we go from here?","authors":"Jacqueline R Harris, Christine W Gao, Jacquelyn F Britton, Carolyn D Applegate, Hans T Bjornsson, Jill A Fahrner","doi":"10.1007/s00439-023-02537-1","DOIUrl":"10.1007/s00439-023-02537-1","url":null,"abstract":"<p><p>The multidisciplinary Epigenetics and Chromatin Clinic at Johns Hopkins provides comprehensive medical care for individuals with rare disorders that involve disrupted epigenetics. Initially centered on classical imprinting disorders, the focus shifted to the rapidly emerging group of genetic disorders resulting from pathogenic germline variants in epigenetic machinery genes. These are collectively called the Mendelian disorders of the epigenetic machinery (MDEMs), or more broadly, Chromatinopathies. In five years, 741 clinic visits have been completed for 432 individual patients, with 153 having confirmed epigenetic diagnoses. Of these, 115 individuals have one of 26 MDEMs with every single one exhibiting global developmental delay and/or intellectual disability. This supports prior observations that intellectual disability is the most common phenotypic feature of MDEMs. Additional common phenotypes in our clinic include growth abnormalities and neurodevelopmental issues, particularly hypotonia, attention-deficit/hyperactivity disorder (ADHD), and anxiety, with seizures and autism being less common. Overall, our patient population is representative of the broader group of MDEMs and includes mostly autosomal dominant disorders impacting writers more so than erasers, readers, and remodelers of chromatin marks. There is an increased representation of dual function components with a reader and an enzymatic domain. As expected, diagnoses were made mostly by sequencing but were aided in some cases by DNA methylation profiling. Our clinic has helped to facilitate the discovery of two new disorders, and our providers are actively developing and implementing novel therapeutic strategies for MDEMs. These data and our high follow-up rate of over 60% suggest that we are achieving our mission to diagnose, learn from, and provide optimal care for our patients with disrupted epigenetics.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10034257/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9387286","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":"H2A monoubiquitination: insights from human genetics and animal models.","authors":"Charles W Ryan, Emily R Peirent, Samantha L Regan, Alba Guxholli, Stephanie L Bielas","doi":"10.1007/s00439-023-02557-x","DOIUrl":"10.1007/s00439-023-02557-x","url":null,"abstract":"<p><p>Metazoan development arises from spatiotemporal control of gene expression, which depends on epigenetic regulators like the polycomb group proteins (PcG) that govern the chromatin landscape. PcG proteins facilitate the addition and removal of histone 2A monoubiquitination at lysine 119 (H2AK119ub1), which regulates gene expression, cell fate decisions, cell cycle progression, and DNA damage repair. Regulation of these processes by PcG proteins is necessary for proper development, as pathogenic variants in these genes are increasingly recognized to underly developmental disorders. Overlapping features of developmental syndromes associated with pathogenic variants in specific PcG genes suggest disruption of central developmental mechanisms; however, unique clinical features observed in each syndrome suggest additional non-redundant functions for each PcG gene. In this review, we describe the clinical manifestations of pathogenic PcG gene variants, review what is known about the molecular functions of these gene products during development, and interpret the clinical data to summarize the current evidence toward an understanding of the genetic and molecular mechanism.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9755067","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":"Nuclear speckleopathies: developmental disorders caused by variants in genes encoding nuclear speckle proteins.","authors":"Kelly E Regan-Fendt, Kosuke Izumi","doi":"10.1007/s00439-023-02540-6","DOIUrl":"10.1007/s00439-023-02540-6","url":null,"abstract":"<p><p>Nuclear speckles are small, membrane-less organelles that reside within the nucleus. Nuclear speckles serve as a regulatory hub coordinating complex RNA metabolism steps including gene transcription, pre-mRNA splicing, RNA modifications, and mRNA nuclear export. Reflecting the importance of proper nuclear speckle function in regulating normal human development, an increasing number of genetic disorders have been found to result from mutations in the genes encoding nuclear speckle proteins. To denote this growing class of genetic disorders, we propose \"nuclear speckleopathies\". Notably, developmental disabilities are commonly seen in individuals with nuclear speckleopathies, suggesting the particular importance of nuclear speckles in ensuring normal neurocognitive development. In this review article, a general overview of nuclear speckle function, and the current knowledge of the mechanisms underlying some nuclear speckleopathies, such as ZTTK syndrome, NKAP-related syndrome, TARP syndrome, and TAR syndrome, are discussed. These nuclear speckleopathies represent valuable models to understand the basic function of nuclear speckles and how its functional defects result in human developmental disorders.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9122590","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":"DNA methylation signatures for chromatinopathies: current challenges and future applications.","authors":"Zain Awamleh, Sarah Goodman, Sanaa Choufani, Rosanna Weksberg","doi":"10.1007/s00439-023-02544-2","DOIUrl":"10.1007/s00439-023-02544-2","url":null,"abstract":"<p><p>Pathogenic variants in genes that encode epigenetic regulators are the cause for more than 100 rare neurodevelopmental syndromes also termed \"chromatinopathies\". DNA methylation signatures, syndrome-specific patterns of DNA methylation alterations, serve as both a research avenue for elucidating disease pathophysiology and a clinical diagnostic tool. The latter is well established, especially for the classification of variants of uncertain significance (VUS). In this perspective, we describe the seminal DNA methylation signature research in chromatinopathies; the complex relationships between genotype, phenotype and DNA methylation, and the future applications of DNA methylation signatures.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11078831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9622007","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":"Histone 3.3-related chromatinopathy: missense variants throughout H3-3A and H3-3B cause a range of functional consequences across species.","authors":"Laura Bryant, Annabel Sangree, Kelly Clark, Elizabeth Bhoj","doi":"10.1007/s00439-023-02536-2","DOIUrl":"10.1007/s00439-023-02536-2","url":null,"abstract":"<p><p>There has been considerable recent interest in the role that germline variants in histone genes play in Mendelian syndromes. Specifically, missense variants in H3-3A and H3-3B, which both encode Histone 3.3, were discovered to cause a novel neurodevelopmental disorder, Bryant-Li-Bhoj syndrome. Most of the causative variants are private and scattered throughout the protein, but all seem to have either a gain-of-function or dominant negative effect on protein function. This is highly unusual and not well understood. However, there is extensive literature about the effects of Histone 3.3 mutations in model organisms. Here, we collate the previous data to provide insight into the elusive pathogenesis of missense variants in Histone 3.3.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10821350","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}