{"title":"光学基因组定位和新一代测序鉴定先天性角化不良中反转录转座子插入和错义变异破坏PARN基因","authors":"Qiaoyu Cao, Anqi Zhao, Zhoukai Long, Xinyi Wang, Chaolan Pan, Yumeng Wang, Wei He, Haisheng Huang, Fuying Chen, Chenfei Wang, Xiaoxiao Wang, Luming Sun, Jingjun Zhao, Ming Li","doi":"10.1155/humu/9290736","DOIUrl":null,"url":null,"abstract":"<p>Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome characterized by defects in telomere biology and clinical manifestations such as nail dystrophy, skin pigmentation abnormalities, and mucosal leukoplakia. Here, using whole exome sequencing (WES), whole genome sequencing (WGS), optical mapping sequencing (OGM), third-generation sequencing, and mRNA sequencing, we diagnosed a participant with <i>PARN</i> gene complex compound heterozygous variants. In addition, protein structure simulation, immunohistochemistry, and western blot were conducted to investigate the structure and expression level of the PARN protein. WES revealed a maternal <i>PARN</i> variant, c.204G>T (p.Gln68His) (NM_002582.3). An insertion variant in the <i>PARN</i> gene from the father was identified by OGM and mRNA sequencing. Third-generation sequencing results determined the insertion position of the SINE-VNTR-Alu (SVA) transposon and its size (2537 bp), which was found to lead to a premature stop codon (p.Gly469delinsGlu∗). The PARN protein level of the parents was reduced due to complex heterozygous variants. Overall, OGM diagnosed the structural variants of the participant with DC, supplementing the disease variant spectrum of DC. This case highlights a novel disease-causing structural variant and the importance of transposon analysis in a clinical diagnostic setting.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.7000,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/9290736","citationCount":"0","resultStr":"{\"title\":\"Optical Genomic Mapping and Next-Generation Sequencing Identified Retrotransposon Insertion and Missense Variant Disrupting PARN Gene in Dyskeratosis Congenita\",\"authors\":\"Qiaoyu Cao, Anqi Zhao, Zhoukai Long, Xinyi Wang, Chaolan Pan, Yumeng Wang, Wei He, Haisheng Huang, Fuying Chen, Chenfei Wang, Xiaoxiao Wang, Luming Sun, Jingjun Zhao, Ming Li\",\"doi\":\"10.1155/humu/9290736\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome characterized by defects in telomere biology and clinical manifestations such as nail dystrophy, skin pigmentation abnormalities, and mucosal leukoplakia. Here, using whole exome sequencing (WES), whole genome sequencing (WGS), optical mapping sequencing (OGM), third-generation sequencing, and mRNA sequencing, we diagnosed a participant with <i>PARN</i> gene complex compound heterozygous variants. In addition, protein structure simulation, immunohistochemistry, and western blot were conducted to investigate the structure and expression level of the PARN protein. WES revealed a maternal <i>PARN</i> variant, c.204G>T (p.Gln68His) (NM_002582.3). An insertion variant in the <i>PARN</i> gene from the father was identified by OGM and mRNA sequencing. Third-generation sequencing results determined the insertion position of the SINE-VNTR-Alu (SVA) transposon and its size (2537 bp), which was found to lead to a premature stop codon (p.Gly469delinsGlu∗). The PARN protein level of the parents was reduced due to complex heterozygous variants. Overall, OGM diagnosed the structural variants of the participant with DC, supplementing the disease variant spectrum of DC. This case highlights a novel disease-causing structural variant and the importance of transposon analysis in a clinical diagnostic setting.</p>\",\"PeriodicalId\":13061,\"journal\":{\"name\":\"Human Mutation\",\"volume\":\"2025 1\",\"pages\":\"\"},\"PeriodicalIF\":3.7000,\"publicationDate\":\"2025-08-22\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/9290736\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Human Mutation\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1155/humu/9290736\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"GENETICS & HEREDITY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Human Mutation","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1155/humu/9290736","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
引用次数: 0
摘要
先天性角化不良症(DC)是一种遗传性骨髓衰竭综合征,以端粒生物学缺陷和指甲营养不良、皮肤色素沉着异常、黏膜白斑等临床表现为特征。通过全外显子组测序(WES)、全基因组测序(WGS)、光学定位测序(OGM)、第三代测序和mRNA测序,我们诊断了一位患有PARN基因复合物杂合变异体的参与者。通过蛋白结构模拟、免疫组织化学、western blot等方法研究PARN蛋白的结构及表达水平。WES发现一个母系PARN变异,c.204G>T (p.Gln68His) (NM_002582.3)。通过OGM和mRNA测序鉴定了来自父亲的PARN基因的插入变异。第三代测序结果确定了sin - vntr - alu (SVA)转座子的插入位置及其大小(2537 bp),发现该转座子导致过早终止密码子(p.Gly469delinsGlu∗)。双亲的PARN蛋白水平由于复杂杂合变异体而降低。总体而言,OGM诊断出DC参与者的结构变异,补充了DC的疾病变异谱。这个病例强调了一种新的致病结构变异和转座子分析在临床诊断中的重要性。
Optical Genomic Mapping and Next-Generation Sequencing Identified Retrotransposon Insertion and Missense Variant Disrupting PARN Gene in Dyskeratosis Congenita
Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome characterized by defects in telomere biology and clinical manifestations such as nail dystrophy, skin pigmentation abnormalities, and mucosal leukoplakia. Here, using whole exome sequencing (WES), whole genome sequencing (WGS), optical mapping sequencing (OGM), third-generation sequencing, and mRNA sequencing, we diagnosed a participant with PARN gene complex compound heterozygous variants. In addition, protein structure simulation, immunohistochemistry, and western blot were conducted to investigate the structure and expression level of the PARN protein. WES revealed a maternal PARN variant, c.204G>T (p.Gln68His) (NM_002582.3). An insertion variant in the PARN gene from the father was identified by OGM and mRNA sequencing. Third-generation sequencing results determined the insertion position of the SINE-VNTR-Alu (SVA) transposon and its size (2537 bp), which was found to lead to a premature stop codon (p.Gly469delinsGlu∗). The PARN protein level of the parents was reduced due to complex heterozygous variants. Overall, OGM diagnosed the structural variants of the participant with DC, supplementing the disease variant spectrum of DC. This case highlights a novel disease-causing structural variant and the importance of transposon analysis in a clinical diagnostic setting.
期刊介绍:
Human Mutation is a peer-reviewed journal that offers publication of original Research Articles, Methods, Mutation Updates, Reviews, Database Articles, Rapid Communications, and Letters on broad aspects of mutation research in humans. Reports of novel DNA variations and their phenotypic consequences, reports of SNPs demonstrated as valuable for genomic analysis, descriptions of new molecular detection methods, and novel approaches to clinical diagnosis are welcomed. Novel reports of gene organization at the genomic level, reported in the context of mutation investigation, may be considered. The journal provides a unique forum for the exchange of ideas, methods, and applications of interest to molecular, human, and medical geneticists in academic, industrial, and clinical research settings worldwide.