Chimeric CYP21A1P/CYP21A2 Genes in 21-Hydroxylase Deficiency Detected by Long-Read Sequencing and Phenotypes Correlation.

IF 5.1 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Xiaoxia Zhang, Yinjie Gao, Lin Lu, Yaqing Cao, Wei Zhang, Xueyan Wu, Anli Tong, Shi Chen, Xi Wang, Jiangfeng Mao, Min Nie
{"title":"Chimeric CYP21A1P/CYP21A2 Genes in 21-Hydroxylase Deficiency Detected by Long-Read Sequencing and Phenotypes Correlation.","authors":"Xiaoxia Zhang, Yinjie Gao, Lin Lu, Yaqing Cao, Wei Zhang, Xueyan Wu, Anli Tong, Shi Chen, Xi Wang, Jiangfeng Mao, Min Nie","doi":"10.1210/clinem/dgae819","DOIUrl":null,"url":null,"abstract":"<p><strong>Context: </strong>21-Hydroxylase deficiency (21-OHD) is caused by pathogenic variants in CYP21A2. High homology between CYP21A2 and its pseudogene CYP21A1P causes mismatches, leading to deletions and CYP21A1P/CYP21A2 chimeras.</p><p><strong>Objective: </strong>To detect chimeric CYP21A1P/CYP21A2 in 21-OHD patients using long-read sequencing (LRS) and analyze genotype-phenotype correlations.</p><p><strong>Methods: </strong>From 2015 to 2023, 869 21-OHD patients were enrolled at Peking Union Medical College Hospital, with 113 identified harboring CYP21A2 large deletion. Long-range PCR and LRS were used to identify the types of CYP21A1P/CYP21A2 chimeric. Haplotype analysis explored founder effects, and in vitro assays assessed the functional impact of novel mutations. Clinical data were retrospectively collected and patients were classified into 4 groups based on genotypes and residual enzyme activity to study genotype-phenotype correlations.</p><p><strong>Results: </strong>Ten types of chimeric CYP21A1P/CYP21A2 genes were identified across 119 alleles, including a novel type, CH-10. The most common, CH-1, accounted for 50.4% of all types. Haplotype analysis of 24 SNPs within CYP21A1P/CYP21A2 CH-1 revealed 25 haplotypes, with haplotype 11 being the most prevalent. Variants p.L100P and p.L301V of CYP21A2 showed enzyme activities of 1.36 ± 0.44% or 1.63 ± 0.19% for 17-hydroxyprogesterone to 11-deoxycortisol, and 1.36 ± 0.58% or 3.99 ± 1.09% for progesterone to 11-deoxycorticosterone, respectively, linked to the simple virilizing type. Genotype-phenotype consistency rates were 78.6% to 84% across the 4 groups.</p><p><strong>Conclusion: </strong>LRS is a comprehensive genetic testing method for 21-OHD patients, effectively detecting both CYP21A2 gene variants and CYP21A1P/CYP21A2 chimeric gene types. This study expands the CYP21A2 variant spectrum by identifying a novel chimera. Haplotype analysis revealed diverse haplotypes for each chimeric gene type, suggesting the absence of a common founder effect. The strong genotype-phenotype correlation aids genetic counseling and supports personalized treatment.</p>","PeriodicalId":50238,"journal":{"name":"Journal of Clinical Endocrinology & Metabolism","volume":" ","pages":"e3322-e3333"},"PeriodicalIF":5.1000,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Clinical Endocrinology & Metabolism","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1210/clinem/dgae819","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
引用次数: 0

Abstract

Context: 21-Hydroxylase deficiency (21-OHD) is caused by pathogenic variants in CYP21A2. High homology between CYP21A2 and its pseudogene CYP21A1P causes mismatches, leading to deletions and CYP21A1P/CYP21A2 chimeras.

Objective: To detect chimeric CYP21A1P/CYP21A2 in 21-OHD patients using long-read sequencing (LRS) and analyze genotype-phenotype correlations.

Methods: From 2015 to 2023, 869 21-OHD patients were enrolled at Peking Union Medical College Hospital, with 113 identified harboring CYP21A2 large deletion. Long-range PCR and LRS were used to identify the types of CYP21A1P/CYP21A2 chimeric. Haplotype analysis explored founder effects, and in vitro assays assessed the functional impact of novel mutations. Clinical data were retrospectively collected and patients were classified into 4 groups based on genotypes and residual enzyme activity to study genotype-phenotype correlations.

Results: Ten types of chimeric CYP21A1P/CYP21A2 genes were identified across 119 alleles, including a novel type, CH-10. The most common, CH-1, accounted for 50.4% of all types. Haplotype analysis of 24 SNPs within CYP21A1P/CYP21A2 CH-1 revealed 25 haplotypes, with haplotype 11 being the most prevalent. Variants p.L100P and p.L301V of CYP21A2 showed enzyme activities of 1.36 ± 0.44% or 1.63 ± 0.19% for 17-hydroxyprogesterone to 11-deoxycortisol, and 1.36 ± 0.58% or 3.99 ± 1.09% for progesterone to 11-deoxycorticosterone, respectively, linked to the simple virilizing type. Genotype-phenotype consistency rates were 78.6% to 84% across the 4 groups.

Conclusion: LRS is a comprehensive genetic testing method for 21-OHD patients, effectively detecting both CYP21A2 gene variants and CYP21A1P/CYP21A2 chimeric gene types. This study expands the CYP21A2 variant spectrum by identifying a novel chimera. Haplotype analysis revealed diverse haplotypes for each chimeric gene type, suggesting the absence of a common founder effect. The strong genotype-phenotype correlation aids genetic counseling and supports personalized treatment.

通过长读测序发现的21-羟化酶缺乏症中的嵌合CYP21A1P/CYP21A2基因与表型的相关性。
背景:21-羟化酶缺乏症(21-OHD)是由CYP21A2的致病变异引起的。CYP21A2与其假基因CYP21A1P高度同源性导致错配,导致缺失和CYP21A1P/CYP21A2嵌合。目的:应用长读测序(LRS)技术检测21-OHD患者CYP21A1P/CYP21A2嵌合基因,并分析基因型与表型的相关性。方法:2015 - 2023年北京协和医院共纳入869例21-OHD患者,其中113例存在CYP21A2大缺失。采用远程PCR和LRS对CYP21A1P/CYP21A2嵌合物进行类型鉴定。单倍型分析探索奠基者效应,体外试验评估新突变的功能影响。回顾性收集临床资料,根据基因型和剩余酶活性将患者分为4组,研究基因型与表型的相关性。结果:在119个等位基因中鉴定出10种嵌合CYP21A1P/CYP21A2基因,其中包括一种新类型CH-10。最常见的是CH-1,占所有类型的50.4%。对CYP21A1P/CYP21A2 CH-1中的24个snp进行单倍型分析,共发现25个单倍型,其中单倍型11最为普遍。CYP21A2变异体p.L100P和p.L301V对17-羟孕酮对11-脱氧皮质醇的酶活性分别为1.36±0.44%和1.63±0.19%,对11-脱氧皮质酮的酶活性分别为1.36±0.58%和3.99±1.09%,与单纯男性化型相关。4组的基因型-表型一致性率为78.6% ~ 84%。结论:LRS是一种针对21-OHD患者的综合性基因检测方法,可有效检测CYP21A2基因变异和CYP21A1P/CYP21A2嵌合基因类型。本研究通过鉴定一种新的嵌合体扩展了CYP21A2变异谱。单倍型分析显示,每种嵌合基因类型的单倍型存在差异,表明没有共同的奠基者效应。强烈的基因型-表型相关性有助于遗传咨询和支持个性化治疗。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Journal of Clinical Endocrinology & Metabolism
Journal of Clinical Endocrinology & Metabolism 医学-内分泌学与代谢
CiteScore
11.40
自引率
5.20%
发文量
673
审稿时长
1 months
期刊介绍: The Journal of Clinical Endocrinology & Metabolism is the world"s leading peer-reviewed journal for endocrine clinical research and cutting edge clinical practice reviews. Each issue provides the latest in-depth coverage of new developments enhancing our understanding, diagnosis and treatment of endocrine and metabolic disorders. Regular features of special interest to endocrine consultants include clinical trials, clinical reviews, clinical practice guidelines, case seminars, and controversies in clinical endocrinology, as well as original reports of the most important advances in patient-oriented endocrine and metabolic research. According to the latest Thomson Reuters Journal Citation Report, JCE&M articles were cited 64,185 times in 2008.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信