Human Genetics最新文献_第10页

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":"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.","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

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

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

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 3.8 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":"10.1007/s00439-023-02638-x","url":null,"abstract":"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.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.8,"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":"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 TANK, UNKL, CCL28, and MAP1LC3A were regulated by DNA methylation upon their corresponding promoter regions. Functionally, by overexpressing AP variants of TANK, we found that TANK|55731 could dramatically suppress MDA-MB-231 cell proliferation and migration. Meanwhile, pan-cancer survival analyses suggested that AP variants of TANK provided more accurate prognostic predictive ability than TANK 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.","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

Novel compound heterozygous variants in FANCI cause premature ovarian insufficiency FANCI 中的新型复合杂合变异导致卵巢早衰

IF 5.3 2区生物学

Human Genetics Pub Date : 2024-03-14 DOI: 10.1007/s00439-024-02650-9

{"title":"Novel compound heterozygous variants in FANCI cause premature ovarian insufficiency","authors":"","doi":"10.1007/s00439-024-02650-9","DOIUrl":"https://doi.org/10.1007/s00439-024-02650-9","url":null,"abstract":"<h3>Abstract</h3> Premature ovarian insufficiency (POI) is a common reproductive aging disorder due to a dramatic decline of ovarian function before 40 years of age. Accumulating evidence reveals that genetic defects, particularly those related to DNA damage response, are a crucial contributing factor to POI. We have demonstrated that the functional Fanconi anemia (FA) pathway maintains the rapid proliferation of primordial germ cells to establish a sufficient reproductive reserve by counteracting replication stress, but the clinical implications of this function in human ovarian function remain to be established. Here, we screened the FANCI gene, which encodes a key component for FA pathway activation, in our whole-exome sequencing database of 1030 patients with idiopathic POI, and identified two pairs of novel compound heterozygous variants, c.[97C > T];[1865C > T] and c.[158-2A > G];[c.959A > G], in two POI patients, respectively. The missense variants did not alter FANCI protein expression and nuclear localization, apart from the variant c.158-2A > G causing abnormal splicing and leading to a truncated mutant p.(S54Pfs*5). Furthermore, the four variants all diminished FANCD2 ubiquitination levels and increased DNA damage under replication stress, suggesting that the FANCI variants impaired FA pathway activation and replication stress response. This study first links replication stress response defects with the pathogenesis of human POI, providing a new insight into the essential roles of the FA genes in ovarian function.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"72 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140126598","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

STEAP3 promotes colon cancer cell proliferation and migration via regulating histone acetylation. STEAP3 通过调节组蛋白乙酰化促进结肠癌细胞的增殖和迁移。

IF 5.3 2区生物学

Human Genetics Pub Date : 2024-03-01 Epub Date: 2024-03-13 DOI: 10.1007/s00439-024-02646-5

Jinjuan Lv, Xiaoqian Liu, Zhiwei Sun, Jianfeng Gao, Xiaoqi Yu, Mengyan Zhang, Zhenyu Zhang, Shuangyi Ren, Yunfei Zuo

{"title":"STEAP3 promotes colon cancer cell proliferation and migration via regulating histone acetylation.","authors":"Jinjuan Lv, Xiaoqian Liu, Zhiwei Sun, Jianfeng Gao, Xiaoqi Yu, Mengyan Zhang, Zhenyu Zhang, Shuangyi Ren, Yunfei Zuo","doi":"10.1007/s00439-024-02646-5","DOIUrl":"10.1007/s00439-024-02646-5","url":null,"abstract":"Colorectal cancer (CRC) is the third most prevalent diagnosed cancer in men and second most prevalent cancer in women. H3K27ac alterations are more commonly than gene mutations in colorectal cancer. Most colorectal cancer genes have significant H3K27ac changes, which leads to an over-expression disorder in gene transcription. Over-expression of STEAP3 is involved in a variety of tumors, participating in the regulation of cancer cell proliferation and migration. The purpose of this work is to investigate the role of STEAP3 in the regulation of histone modification (H3K27ac) expression in colon cancer. Bioinformatic ChIP-seq, ChIP-qPCR and ATAC-seq were used to analyze the histone modification properties and gene accessibility of STEAP3. Western blot and qRT-PCR were used to evaluate relative protein and gene expression, respectively. CRISPR/Cas9 technology was used to knockout STEAP3 on colon cancer cells to analyze the effect of ATF3 on STEAP3. STEAP3 was over-expressed in colon cancer and associated with higher metastases and more invasive and worse stage of colon cancer. ChIP-seq and ChIP-qPCR analyses revealed significant enrichment of H3K27ac in the STEAP3 gene. In addition, knocking down STEAP3 significantly inhibits colon cancer cell proliferation and migration and down-regulates H3K27ac expression. ChIP-seq found that ATF3 is enriched in the STEAP3 gene and CRISPR/Cas9 technology used for the deletion of the ATF3 binding site suppresses the expression of STEAP3. Over-expression of STEAP3 promotes colon cancer cell proliferation and migration. Mechanical studies have indicated that H3K27ac and ATF3 are significantly enriched in the STEAP3 gene and regulate the over-expression of STEAP3.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"343-355"},"PeriodicalIF":5.3,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140119343","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

A novel 193-plex MPS panel integrating STRs and SNPs highlights the application value of forensic genetics in individual identification and paternity testing. 一个整合了 STR 和 SNP 的 193 复式 MPS 面板凸显了法医遗传学在个体鉴定和亲子鉴定中的应用价值。

IF 5.3 2区生物学

Human Genetics Pub Date : 2024-03-01 Epub Date: 2024-03-18 DOI: 10.1007/s00439-024-02658-1

Xueyuan Liu, Chengliang Yang, Xiaohui Chen, Xiaolong Han, Hong Liu, Xingkun Zhang, Quyi Xu, Xingyi Yang, Changhui Liu, Ling Chen, Chao Liu

{"title":"A novel 193-plex MPS panel integrating STRs and SNPs highlights the application value of forensic genetics in individual identification and paternity testing.","authors":"Xueyuan Liu, Chengliang Yang, Xiaohui Chen, Xiaolong Han, Hong Liu, Xingkun Zhang, Quyi Xu, Xingyi Yang, Changhui Liu, Ling Chen, Chao Liu","doi":"10.1007/s00439-024-02658-1","DOIUrl":"10.1007/s00439-024-02658-1","url":null,"abstract":"Massively parallel sequencing (MPS) has emerged as a promising technology for targeting multiple genetic loci simultaneously in forensic genetics. Here, a novel 193-plex panel was designed to target 28 A-STRs, 41 Y-STRs, 21 X-STRs, 3 sex-identified loci, and 100 A-SNPs by employing a single-end 400 bp sequencing strategy on the MGISEQ-2000™ platform. In the present study, a series of validations and sequencing of 1642 population samples were performed to evaluate the overall performance of the MPS-based panel and its practicality in forensic application according to the SWGDAM guidelines. In general, the 193-plex markers in our panel showed good performance in terms of species specificity, stability, and repeatability. Compared to commercial kits, this panel achieved 100% concordance for standard gDNA and 99.87% concordance for 14,560 population genotypes. Moreover, this panel detected 100% of the loci from 0.5 ng of DNA template and all unique alleles at a 1:4 DNA mixture ratio (0.2 ng minor contributor), and the applicability of the proposed approach for tracing and degrading DNA was further supported by case samples. In addition, several forensic parameters of STRs and SNPs were calculated in a population study. High CPE and CPD values greater than 0.9999999 were clearly demonstrated and these results could be useful references for the application of this panel in individual identification and paternity testing. Overall, this 193-plex MPS panel has been shown to be a reliable, repeatable, robust, inexpensive, and powerful tool sufficient for forensic practice.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"371-383"},"PeriodicalIF":5.3,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140158051","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

Identification and functional analysis of rare HECTD1 missense variants in human neural tube defects. 人类神经管缺陷中罕见的 HECTD1 错义变体的鉴定和功能分析。

IF 5.3 2区生物学

Human Genetics Pub Date : 2024-03-01 Epub Date: 2024-03-07 DOI: 10.1007/s00439-024-02647-4

Elias Oxman, Huili Li, Hong-Yan Wang, Irene E Zohn

{"title":"Identification and functional analysis of rare HECTD1 missense variants in human neural tube defects.","authors":"Elias Oxman, Huili Li, Hong-Yan Wang, Irene E Zohn","doi":"10.1007/s00439-024-02647-4","DOIUrl":"10.1007/s00439-024-02647-4","url":null,"abstract":"Neural tube defects (NTDs) are severe malformations of the central nervous system that arise from failure of neural tube closure. HECTD1 is an E3 ubiquitin ligase required for cranial neural tube closure in mouse models. NTDs in the Hectd1 mutant mouse model are due to the failure of cranial mesenchyme morphogenesis during neural fold elevation. Our earlier research has linked increased extracellular heat shock protein 90 (eHSP90) secretion to aberrant cranial mesenchyme morphogenesis in the Hectd1 model. Furthermore, overexpression of HECTD1 suppresses stress-induced eHSP90 secretion in cell lines. In this study, we report the identification of five rare HECTD1 missense sequence variants in NTD cases. The variants were found through targeted next-generation sequencing in a Chinese cohort of 352 NTD cases and 224 ethnically matched controls. We present data showing that HECTD1 is a highly conserved gene, extremely intolerant to loss-of-function mutations and missense changes. To evaluate the functional consequences of NTD-associated missense variants, functional assays in HEK293T cells were performed to examine protein expression and the ability of HECTD1 sequence variants to suppress eHSP90 secretion. One NTD-associated variant (A1084T) had significantly reduced expression in HEK293T cells. All five NTD-associated variants (p.M392V, p.T801I, p.I906V, p.A1084T, and p.P1835L) reduced regulation of eHSP90 secretion by HECTD1, while a putative benign variant (p.P2474L) did not. These findings are the first association of HECTD1 sequence variation with NTDs in humans.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"263-277"},"PeriodicalIF":5.3,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11043113/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140049314","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