Human Genetics最新文献

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H2A monoubiquitination: insights from human genetics and animal models. H2A 单泛素化:人类遗传学和动物模型的启示。
IF 3.8 2区 生物学
Human Genetics Pub Date : 2024-04-01 Epub Date: 2023-04-22 DOI: 10.1007/s00439-023-02557-x
Charles W Ryan, Emily R Peirent, Samantha L Regan, Alba Guxholli, Stephanie L Bielas
{"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":" ","pages":"511-527"},"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}
引用次数: 0
Five years of experience in the Epigenetics and Chromatin Clinic: what have we learned and where do we go from here? 在表观遗传学和染色质诊所的5年经验:我们学到了什么,我们将何去何从?
IF 5.3 2区 生物学
Human Genetics Pub Date : 2024-04-01 Epub Date: 2023-03-23 DOI: 10.1007/s00439-023-02537-1
Jacqueline R Harris, Christine W Gao, Jacquelyn F Britton, Carolyn D Applegate, Hans T Bjornsson, Jill A Fahrner
{"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":" ","pages":"607-624"},"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}
引用次数: 0
Nuclear speckleopathies: developmental disorders caused by variants in genes encoding nuclear speckle proteins. 核斑点病:由核斑点蛋白编码基因变异引起的发育障碍。
IF 3.8 2区 生物学
Human Genetics Pub Date : 2024-04-01 Epub Date: 2023-03-16 DOI: 10.1007/s00439-023-02540-6
Kelly E Regan-Fendt, Kosuke Izumi
{"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":" ","pages":"529-544"},"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}
引用次数: 0
Histone 3.3-related chromatinopathy: missense variants throughout H3-3A and H3-3B cause a range of functional consequences across species. 组蛋白 3.3 相关染色质病变:整个 H3-3A 和 H3-3B 的错义变体在不同物种中造成一系列功能性后果。
IF 3.8 2区 生物学
Human Genetics Pub Date : 2024-04-01 Epub Date: 2023-03-03 DOI: 10.1007/s00439-023-02536-2
Laura Bryant, Annabel Sangree, Kelly Clark, Elizabeth Bhoj
{"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":" ","pages":"497-510"},"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}
引用次数: 0
The omics era: a nexus of untapped potential for Mendelian chromatinopathies. 全息时代:孟德尔染色质病未开发潜力的纽带。
IF 3.8 2区 生物学
Human Genetics Pub Date : 2024-04-01 Epub Date: 2023-04-28 DOI: 10.1007/s00439-023-02560-2
Aileen A Nava, Valerie A Arboleda
{"title":"The omics era: a nexus of untapped potential for Mendelian chromatinopathies.","authors":"Aileen A Nava, Valerie A Arboleda","doi":"10.1007/s00439-023-02560-2","DOIUrl":"10.1007/s00439-023-02560-2","url":null,"abstract":"<p><p>The OMICs cascade describes the hierarchical flow of information through biological systems. The epigenome sits at the apex of the cascade, thereby regulating the RNA and protein expression of the human genome and governs cellular identity and function. Genes that regulate the epigenome, termed epigenes, orchestrate complex biological signaling programs that drive human development. The broad expression patterns of epigenes during human development mean that pathogenic germline mutations in epigenes can lead to clinically significant multi-system malformations, developmental delay, intellectual disabilities, and stem cell dysfunction. In this review, we refer to germline developmental disorders caused by epigene mutation as \"chromatinopathies\". We curated the largest number of human chromatinopathies to date and our expanded approach more than doubled the number of established chromatinopathies to 179 disorders caused by 148 epigenes. Our study revealed that 20.6% (148/720) of epigenes cause at least one chromatinopathy. In this review, we highlight key examples in which OMICs approaches have been applied to chromatinopathy patient biospecimens to identify underlying disease pathogenesis. The rapidly evolving OMICs technologies that couple molecular biology with high-throughput sequencing or proteomics allow us to dissect out the causal mechanisms driving temporal-, cellular-, and tissue-specific expression. Using the full repertoire of data generated by the OMICs cascade to study chromatinopathies will provide invaluable insight into the developmental impact of these epigenes and point toward future precision targets for these rare disorders.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"475-495"},"PeriodicalIF":3.8,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11078811/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9357847","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}
引用次数: 0
DNA methylation signatures for chromatinopathies: current challenges and future applications. 染色质病的 DNA 甲基化特征:当前挑战与未来应用。
IF 3.8 2区 生物学
Human Genetics Pub Date : 2024-04-01 Epub Date: 2023-04-06 DOI: 10.1007/s00439-023-02544-2
Zain Awamleh, Sarah Goodman, Sanaa Choufani, Rosanna Weksberg
{"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":" ","pages":"551-557"},"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}
引用次数: 0
Chromatinopathies - from discovery to clinical diagnosis in the real world. 染色质疾病--从发现到临床诊断的真实世界。
IF 3.8 2区 生物学
Human Genetics Pub Date : 2024-04-01 DOI: 10.1007/s00439-024-02665-2
Bianca E Russell, Wen-Hann Tan
{"title":"Chromatinopathies - from discovery to clinical diagnosis in the real world.","authors":"Bianca E Russell, Wen-Hann Tan","doi":"10.1007/s00439-024-02665-2","DOIUrl":"10.1007/s00439-024-02665-2","url":null,"abstract":"","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"471-473"},"PeriodicalIF":3.8,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140859475","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}
引用次数: 0
Interpreting variants in genes affected by clonal hematopoiesis in population data. 解读群体数据中受克隆造血影响的基因变异。
IF 3.8 2区 生物学
Human Genetics Pub Date : 2024-04-01 Epub Date: 2023-02-04 DOI: 10.1007/s00439-023-02526-4
Sanna Gudmundsson, Colleen M Carlston, Anne O'Donnell-Luria
{"title":"Interpreting variants in genes affected by clonal hematopoiesis in population data.","authors":"Sanna Gudmundsson, Colleen M Carlston, Anne O'Donnell-Luria","doi":"10.1007/s00439-023-02526-4","DOIUrl":"10.1007/s00439-023-02526-4","url":null,"abstract":"<p><p>Reference population databases like the Genome Aggregation Database (gnomAD) have improved our ability to interpret the human genome. Variant frequencies and frequency-derived tools (such as depletion scores) have become fundamental to variant interpretation and the assessment of variant-gene-disease relationships. Clonal hematopoiesis (CH) obstructs variant interpretation as somatic variants that provide proliferative advantage will affect variant frequencies, depletion scores, and downstream filtering. Further, default filtering of variants or genes associated with CH risks filtering bona fide germline variants as variants associated with CH can also cause Mendelian conditions. Here, we provide our insights on interpreting population variant data in genes affected by clonal hematopoiesis, as well as recommendations for careful review of 36 established CH genes associated with neurodevelopmental conditions.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"545-549"},"PeriodicalIF":3.8,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10400727/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9942781","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}
引用次数: 0
An AI-based approach driven by genotypes and phenotypes to uplift the diagnostic yield of genetic diseases. 以基因型和表型为驱动力的人工智能方法,提高遗传疾病的诊断率。
IF 5.3 2区 生物学
Human Genetics Pub Date : 2024-03-23 DOI: 10.1007/s00439-023-02638-x
S Zucca, G Nicora, F De Paoli, M G Carta, R Bellazzi, P Magni, E Rizzo, I Limongelli
{"title":"An AI-based approach driven by genotypes and phenotypes to uplift the diagnostic yield of genetic diseases.","authors":"S Zucca, G Nicora, F De Paoli, M G Carta, R Bellazzi, P Magni, E Rizzo, I Limongelli","doi":"10.1007/s00439-023-02638-x","DOIUrl":"https://doi.org/10.1007/s00439-023-02638-x","url":null,"abstract":"<p><p>Identifying disease-causing variants in Rare Disease patients' genome is a challenging problem. To accomplish this task, we describe a machine learning framework, that we called \"Suggested Diagnosis\", whose aim is to prioritize genetic variants in an exome/genome based on the probability of being disease-causing. To do so, our method leverages standard guidelines for germline variant interpretation as defined by the American College of Human Genomics (ACMG) and the Association for Molecular Pathology (AMP), inheritance information, phenotypic similarity, and variant quality. Starting from (1) the VCF file containing proband's variants, (2) the list of proband's phenotypes encoded in Human Phenotype Ontology terms, and optionally (3) the information about family members (if available), the \"Suggested Diagnosis\" ranks all the variants according to their machine learning prediction. This method significantly reduces the number of variants that need to be evaluated by geneticists by pinpointing causative variants in the very first positions of the prioritized list. Most importantly, our approach proved to be among the top performers within the CAGI6 Rare Genome Project Challenge, where it was able to rank the true causative variant among the first positions and, uniquely among all the challenge participants, increased the diagnostic yield of 12.5% by solving 2 undiagnosed cases.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140193639","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}
引用次数: 0
Genome-wide analyses reveal the regulatory roles of DNA methylation-regulated alternative promoter transcripts in breast cancer 全基因组分析揭示了 DNA 甲基化调控的替代启动子转录本在乳腺癌中的调控作用
IF 5.3 2区 生物学
Human Genetics Pub Date : 2024-03-19 DOI: 10.1007/s00439-024-02653-6
Yingdong Song, Tao Shen, Huihui Sun, Xiangting Wang
{"title":"Genome-wide analyses reveal the regulatory roles of DNA methylation-regulated alternative promoter transcripts in breast cancer","authors":"Yingdong Song, Tao Shen, Huihui Sun, Xiangting Wang","doi":"10.1007/s00439-024-02653-6","DOIUrl":"https://doi.org/10.1007/s00439-024-02653-6","url":null,"abstract":"<p>A certain proportion of genes are regulated by multiple, distinct promoters, revealing a dynamic landscape of the cancer transcriptome. However, the contribution of alternative promoters (APs) in breast cancer (BRCA) remains largely unexplored. Here, we identified 3654 genes with multiple promoters in BRCA patients, and 53 of them could generate distinct AP transcripts that are dysregulated and prognosis-related in BRCA, namely prognosis-related dysregulated AP (prdeAP) transcripts. Interestingly, when we searched for the genomic signatures of these prdeAP genes, we found that the promoter regions of 92% of the prdeAP genes were enriched with abundant DNA methylation signals. Through further bioinformatic analysis and experimental validation, we showed that AP selections of <i>TANK</i>, <i>UNKL</i>, <i>CCL28</i>, and <i>MAP1LC3A</i> were regulated by DNA methylation upon their corresponding promoter regions. Functionally, by overexpressing AP variants of <i>TANK</i>, we found that <i>TANK|55731</i> could dramatically suppress MDA-MB-231 cell proliferation and migration. Meanwhile, pan-cancer survival analyses suggested that AP variants of <i>TANK</i> provided more accurate prognostic predictive ability than <i>TANK</i> gene in a variety of tumor types, including BRCA. Together, by uncovering the DNA methylation-regulated AP transcripts with tumor prognostic features, our work revealed a novel layer of regulators in BRCA progression and provided potential targets that served as effective biomarkers for anti-BRCA treatment.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"26 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140168079","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}
引用次数: 0
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