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Article(id=1198619423213978100, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1198619422425448948, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.2548.2023.1227, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1670428800000, receivedDateStr=2022-12-08, revisedDate=null, revisedDateStr=null, acceptedDate=1675785600000, acceptedDateStr=2023-02-08, onlineDate=1763702739765, onlineDateStr=2025-11-21, pubDate=1716825600000, pubDateStr=2024-05-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1763702739765, onlineIssueDateStr=2025-11-21, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1763702739765, creator=13701087609, updateTime=1763702739765, updator=13701087609, issue=Issue{id=1198619422425448948, tenantId=1146029695717560320, journalId=1189873630562394117, year='2024', volume='49', issue='5', pageStart='489', pageEnd='610', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1763702739578, creator=13701087609, updateTime=1763702927730, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1198620211667628088, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1198619422425448948, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1198620211667628089, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1198619422425448948, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=495, endPage=503, ext={EN=ArticleExt(id=1198619423541133816, articleId=1198619423213978100, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Analysis on genetic etiology of disorders of sex development using whole exome sequencing, columnId=1190310109000602400, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Clinical Research, runingTitle=null, highlight=null, articleAbstract=

Objective To elucidate the molecular genetic etiology of patients with disorders of sex development (DSD) using whole exome sequencing (WES), thereby enhancing our understanding of the underlying mechanisms of sexual development abnormalities. Methods Retrospective analysis was conducted on clinical data of 60 DSD patients diagnosed in the First People's Hospital of Yunnan Province between March 2008 and August 2021, with an additional family study for one proband. Genomic DNA was extracted from patients for WES analysis. Single nucleotide polymorphism (SNP) and insertions/deletion (InDel) tests were identified using SAMtools software in conjunction with established SNP and InDel databases. Copy number variations (CNVs) at the exon level were detected using ExomeDepth, while the potential pathogenicity of mutations was predicted with PolyPhen-2, Mutation taster and PyMol software, with Sanger sequencing employed for confirmation. Results The study included 22 patients with 46,XX DSD and 38 with 46,XY DSD. Among the 46,XX DSD patients, the SRY gene was detected in 14 patients. In the remaining 8 patients and a proband's families, single nucleotide site variations (SNVs) of NR5A1, PROKR2 and ANOS1 genes were identified in 2 patients, and CNVs in CYP21A2 gene were found in 4 patients. The pathogenicity of CYP21A2 EX1 Dup has been previously reported, while the remaining 3 CNVs were of uncertain significance, and no DSD-related mutations were detected in 2 patients. In the WES analysis of 46,XY DSD patients, 10 pathogenic or likely pathogenic SNVs across 5 genes (SRY, AR, SRD5A2, CYP17A1, and NR5A1) were identified in 14 patients. Additionally, 5 likely pathogenic CNVs involving the CYP21A2, AKR1C2, CBX2, and NR5A1 genes were detected in 5 patients, comprising 3 deletions and 2 duplications. Novel SNVs in NR5A1 (c.722G>T, c.48C>G) and ANOS1 c.564A>T were identified, with no prior reports in relevant databases. The pathogenicity of CYP21A2 EX1 Dup is documented in related databases, while the remaining CNVs have not been previously reported. Conclusion The utilization of WES technology has enhanced the diagnostic potential for DSD, broadened the spectrum of known DSD-related gene mutations, and deepened our comprehension of DSD pathogenesis, offering valuable support for genetic counseling.

, correspAuthors=Jing He, authorNote=null, correspAuthorsNote=
E-mail:
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目的 通过全外显子组测序(WES)技术分析性发育异常(DSD)患者的分子遗传学病因，以加深对DSD致病机制的认识。方法 收集2008年3月-2021年8月于云南省第一人民医院就诊的60例DSD患者的临床资料进行回顾性分析，并对其中1个先证者进行家系研究。提取所有患者的外周血基因组DNA进行WES测序分析，WES结果利用SAMtools软件、单核苷酸多态性(SNP)数据库、InDel数据库进行SNP和InDel检测；采用ExomeDepth进行外显子水平的拷贝数变异(CNV)检测；应用PolyPhen-2、Mutation taster、PyMol软件进行突变的有害性预测，并采用Sanger进行测序验证。结果 60例DSD患者中，22例为46,XX DSD，38例为46,XY DSD。22例46,XX DSD患者中14例存在SRY基因；在另外8例患者和其中1个先证者家系中，2例患者的NR5A1、PROKR2和ANOS1基因发生单核苷酸变异(SNV)，4例患者中的CYP21A2基因发生CNV，其中CYP21A2 EX1 Dup已有该变异的相关致病性报道，其余3个CNV为意义未明的变异，2例未检出与DSD相关的基因突变位点。38例46,XY DSD患者WES分析结果中，14例中检出了10个致病或疑似致病变异位点，包括SRY、AR、SRD5A2、CYP17A1、NR5A1等5个基因；5例中检出CYP21A2、AKR1C2、CBX2、NR5A1基因的5个疑似致病的CNV，其中3个微缺失，2个微重复。WES结果中NR5A1(c.722G>T、c.48C>G)、ANOS1 c.564A>T变异为首次报道的位点，在检出的CNV中，CYP21A2 EX1 Dup在相关数据库中有致病性的报道，其余未见报道。结论 WES技术的应用提高了对DSD的诊断能力，拓展了现有的DSD相关致病基因突变谱数据，丰富了对DSD致病机制的认识，可为开展遗传咨询提供帮助。

, correspAuthors=贺静, authorNote=null, correspAuthorsNote=
贺静，E-mail：
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吴柳娇，硕士研究生，主要从事医学遗传学方面的研究

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吴柳娇，硕士研究生，主要从事医学遗传学方面的研究

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吴柳娇，硕士研究生，主要从事医学遗传学方面的研究

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Proc Natl Acad Sci U S A,2013, 110(38): E3567-E3576., articleTitle=Inherited human sex reversal due to impaired nucleocytoplasmic trafficking of SRY defines a male transcriptional threshold, refAbstract=null), Reference(id=1198630240638563178, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619423213978100, doi=null, pmid=null, pmcid=null, year=2023, volume=96, issue=2, pageStart=144, pageEnd=168, url=null, language=null, rfNumber=[21], rfOrder=20, authorNames=McElreavey K, Bashamboo A, journalName=Horm Res Paediatr, refType=null, unstructuredReference=McElreavey K, Bashamboo A. Monogenic forms of DSD: an update[J]. 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South Dartmouth (MA): MDText.com, Inc. 2022., articleTitle=XY Differences of Sexual Development, refAbstract=null), Reference(id=1198630241842328430, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619423213978100, doi=null, pmid=null, pmcid=null, year=2012, volume=97, issue=7, pageStart=E1294, pageEnd=E1306, url=null, language=null, rfNumber=[23], rfOrder=22, authorNames=Camats N, Pandey AV, Fernández-Cancio M, journalName=J Clin Endocrinol Metab, refType=null, unstructuredReference=Camats N, Pandey AV, Fernández-Cancio M, et al. Ten novel mutations in the NR5A1 gene cause disordered sex development in 46, XY and ovarian insufficiency in 46, XX individuals[J]. J Clin Endocrinol Metab, 2012, 97(7): E1294-E1306., articleTitle=Ten novel mutations in the NR5A1 gene cause disordered sex development in 46, XY and ovarian insufficiency in 46, XX individuals, refAbstract=null), Reference(id=1198630241938797424, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619423213978100, doi=null, pmid=null, pmcid=null, year=2018, volume=65, issue=12, pageStart=1187, pageEnd=1192, url=null, language=null, rfNumber=[24], rfOrder=23, authorNames=Adachi M, Hasegawa T, Tanaka Y, journalName=Endocr J, refType=null, unstructuredReference=Adachi M, Hasegawa T, Tanaka Y, et al. Spontaneous virilization around puberty in NR5A1-related 46, XY sex reversal: additional case and a literature review[J]. Endocr J, 2018, 65(12): 1187-1192., articleTitle=Spontaneous virilization around puberty in NR5A1-related 46, XY sex reversal: additional case and a literature review, refAbstract=null), Reference(id=1198630242018489202, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619423213978100, doi=null, pmid=null, pmcid=null, year=2012, volume=380, issue=9851, pageStart=1419, pageEnd=1428, url=null, language=null, rfNumber=[25], rfOrder=24, authorNames=Hughes IA, Davies JD, Bunch TI, journalName=Lancet, refType=null, unstructuredReference=Hughes IA, Davies JD, Bunch TI, et al. Androgen insensitivity syndrome[J]. Lancet, 2012, 380(9851): 1419-1428., articleTitle=Androgen insensitivity syndrome, refAbstract=null), Reference(id=1198630242085598068, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619423213978100, doi=null, pmid=null, pmcid=null, year=2017, volume=30, issue=1, pageStart=19, pageEnd=26, url=null, language=null, rfNumber=[26], rfOrder=25, authorNames=Ittiwut C, Pratuangdejkul J, Supornsilchai V, journalName=J Pediatr Endocrinol Metab, refType=null, unstructuredReference=Ittiwut C, Pratuangdejkul J, Supornsilchai V, et al. Novel mutations of the SRD5A2 and AR genes in Thai patients with 46, XY disorders of sex development[J]. J Pediatr Endocrinol Metab, 2017, 30(1): 19-26., articleTitle=Novel mutations of the SRD5A2 and AR genes in Thai patients with 46, XY disorders of sex development, refAbstract=null), Reference(id=1198630242182067061, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619423213978100, doi=null, pmid=null, pmcid=null, year=2020, volume=16, issue=5, pageStart=689.e1, pageEnd=689.e12, url=null, language=null, rfNumber=[27], rfOrder=26, authorNames=Mares L, Vilchis F, Chávez B, journalName=J Pediatr Urol, refType=null, unstructuredReference=Mares L, Vilchis F, Chávez B, et al. Molecular genetic analysis of AKR1C2-4 and HSD17B6 genes in subjects 46, XY with hypospadias[J]. J Pediatr Urol, 2020, 16(5): 689.e1-689.e12., articleTitle=Molecular genetic analysis of AKR1C2-4 and HSD17B6 genes in subjects 46, XY with hypospadias, refAbstract=null)], funds=[Fund(id=1198630238356861754, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619423213978100, awardId=81860030, language=EN, fundingSource=National Natural Science Foundation of China(81860030), fundOrder=null, country=null), Fund(id=1198630238465913662, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619423213978100, awardId=81860030, language=CN, fundingSource=国家自然科学基金(81860030), fundOrder=null, country=null), Fund(id=1198630238566576960, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619423213978100, awardId=2019HB071, language=EN, fundingSource=Yunnan Provincial Technological Innovation Talent Training Project(2019HB071), fundOrder=null, country=null), Fund(id=1198630238717571907, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619423213978100, awardId=2019HB071, language=CN, fundingSource=云南省技术创新人才培养项目(2019HB071), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1198630231734055567, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619423213978100, xref=1, ext=[AuthorCompanyExt(id=1198630231742444176, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619423213978100, companyId=1198630231734055567, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1Medical School , Kunming University of Science and Technology, Kunming, Yunnan 650500, China), AuthorCompanyExt(id=1198630231750832785, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619423213978100, companyId=1198630231734055567, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1昆明理工大学医学院，云南昆明 650500)]), AuthorCompany(id=1198630232837157528, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619423213978100, xref=2, ext=[AuthorCompanyExt(id=1198630232858129050, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619423213978100, companyId=1198630232837157528, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2Department of Medical Genetics, the First People's Hospital of Yunnan Province/Key Laboratory of National Health Commission for Pre-pregnancy Eugenics in Western China, Kunming, Yunnan 650500, China), AuthorCompanyExt(id=1198630232883294875, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619423213978100, companyId=1198630232837157528, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2云南省第一人民医院医学遗传科/国家卫生健康委西部孕前优生重点实验室，云南昆明 650500)])], figs=[ArticleFig(id=1198630235970302743, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619423213978100, language=EN, label=Fig.1, caption=Analysis of genetic test results of proband 71 and proband's parents, figureFileSmall=fhLmAqOu3eJIGboXJ+iiUQ==, figureFileBig=12kyLHLT1wnhzHZoifnFFA==, tableContent=null), ArticleFig(id=1198630236070966041, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619423213978100, language=CN, label=图1, caption=先证者71及其父母基因检测结果分析

A. ANOS1 c.564A>T(p.K188N)、PROKR2 c.253C>T(p.R85C)Sanger测序图，左侧源于母亲，右侧源于父亲；B. ANOS1蛋白结构模拟预测；C. ANOS1 c.564A>T(p.K188N)突变位点的保守性分析；D. PolyPhen-2、Mutation taster评估ANOS1 c.564A>T(p.K188N)的致病性[HumDiv： Probably damaging=1(很可能有害，分值≥0.909)、HumVar： Probably damaging=1(很可能有害，分值≥0.957)]

, figureFileSmall=fhLmAqOu3eJIGboXJ+iiUQ==, figureFileBig=12kyLHLT1wnhzHZoifnFFA==, tableContent=null), ArticleFig(id=1198630236150657820, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619423213978100, language=EN, label=Fig.2, caption=Pathways of sexual development and related genes, figureFileSmall=d/gRFY9dlJhfcfdAu/kXIA==, figureFileBig=i30/590nH3eG8hyuwKMkWA==, tableContent=null), ArticleFig(id=1198630236213572383, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619423213978100, language=CN, label=图2, caption=性发育途径及相关的基因, figureFileSmall=d/gRFY9dlJhfcfdAu/kXIA==, figureFileBig=i30/590nH3eG8hyuwKMkWA==, tableContent=null), ArticleFig(id=1198630237295702819, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619423213978100, language=EN, label=Tab.1, caption=

Genetic characteristics of SNV in 46,XX DSD patients

, figureFileSmall=null, figureFileBig=null, tableContent=
患者编号基因cDNA碱基序列改变蛋白质氨基酸改变是否报道过染色体位置基因型变异类型致病性分类遗传模式相关疾病
40NR5A1c.48C>Gp.C16W否chr9杂合错义变异VUSAD46,XX性反转4型
71PROKR2c.253C>Tp.R85C是chr20杂合错义变异VUSADKallmann综合征3型
ANOS1c.564A>TP.K188N否chrX杂合错义变异VUSXLKallmann综合征1型
), ArticleFig(id=1198630237392171814, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619423213978100, language=CN, label=表1, caption=

46,XX DSD患者SNV遗传学特征

, figureFileSmall=null, figureFileBig=null, tableContent=
患者编号基因cDNA碱基序列改变蛋白质氨基酸改变是否报道过染色体位置基因型变异类型致病性分类遗传模式相关疾病
40NR5A1c.48C>Gp.C16W否chr9杂合错义变异VUSAD46,XX性反转4型
71PROKR2c.253C>Tp.R85C是chr20杂合错义变异VUSADKallmann综合征3型
ANOS1c.564A>TP.K188N否chrX杂合错义变异VUSXLKallmann综合征1型
), ArticleFig(id=1198630237471863594, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619423213978100, language=EN, label=Tab.2, caption=

Genetic characteristics of CNV in 46,XX DSD patients

, figureFileSmall=null, figureFileBig=null, tableContent=
患者编号基因染色体位置转录本编号氨基酸变化基因亚区遗传模式致病性分类相关疾病
75CYP21A2chr6：32006092-32006401NM_000500.7：EX1 DupEX1ARVUS21-羟化酶缺乏性先天性肾上腺皮质增生症
chr6：32008646-32009447NM_000500.7：EX10E DupEX10EARVUS
6CYP21A2chr6：32006201-32007982NM_000500.7：EX1-EX7 DupEX1-EX7ARVUS
27CYP21A2chr6：32007783-32008548NM_000500.7：EX7-EX9 DupEX7-EX9ARVUS
15CYP21A2chr6：32008184-32010608NM_000500.7：EX8-EX10E DupEX8-EX10EARVUS
), ArticleFig(id=1198630237610275629, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619423213978100, language=CN, label=表2, caption=

46,XX DSD患者CNV遗传学特征

, figureFileSmall=null, figureFileBig=null, tableContent=
患者编号基因染色体位置转录本编号氨基酸变化基因亚区遗传模式致病性分类相关疾病
75CYP21A2chr6：32006092-32006401NM_000500.7：EX1 DupEX1ARVUS21-羟化酶缺乏性先天性肾上腺皮质增生症
chr6：32008646-32009447NM_000500.7：EX10E DupEX10EARVUS
6CYP21A2chr6：32006201-32007982NM_000500.7：EX1-EX7 DupEX1-EX7ARVUS
27CYP21A2chr6：32007783-32008548NM_000500.7：EX7-EX9 DupEX7-EX9ARVUS
15CYP21A2chr6：32008184-32010608NM_000500.7：EX8-EX10E DupEX8-EX10EARVUS
), ArticleFig(id=1198630237731910448, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619423213978100, language=EN, label=Tab.3, caption=

Genetic characteristics of SNV in 46,XY DSD patients

, figureFileSmall=null, figureFileBig=null, tableContent=
患者编号基因核苷酸改变氨基酸改变新生变异染色体位置基因型突变类型致病性分类遗传模式相关疾病
4、19、20ARc.1846C>Tp.R616C否chrX半合错义变异LPXL

(1)雄激素不敏感综合征
(2)部分雄激素不敏感症
(3)X连锁尿道下裂1型

7、10、37c.2567G>Ap.R856H否chrX半合错义变异LPXL
43c.2566C>Tp.R856C否chrX半合错义变异LPXL
55c.2318+1G>A否chrX半合剪接变异LPXL
58c.2343G>Ap.M781I否chrX半合错义变异LPXL
18SRD5A2c.16C>Tp.Q6*否chr2纯合无义变异LPAR类固醇5-α还原酶缺乏症
36c.282-2A>G否chr2纯合剪接变异LPAR
56CYP17A1c.297+2T>C否chr10纯合剪接变异LP`AR17,20裂解酶缺乏性先天性肾上腺皮质增生症
42NR5A1c.722G>Tp.Q258*是chr9杂合无义变异LPAD46,XY性反转3型
59SRYc.178G>Cp.V60L否chrY半合错义变异PYL46,XY性反转1型
), ArticleFig(id=1198630237811602223, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619423213978100, language=CN, label=表3, caption=

46,XY DSD患者SNV遗传学特征

, figureFileSmall=null, figureFileBig=null, tableContent=
患者编号基因核苷酸改变氨基酸改变新生变异染色体位置基因型突变类型致病性分类遗传模式相关疾病
4、19、20ARc.1846C>Tp.R616C否chrX半合错义变异LPXL

(1)雄激素不敏感综合征
(2)部分雄激素不敏感症
(3)X连锁尿道下裂1型

7、10、37c.2567G>Ap.R856H否chrX半合错义变异LPXL
43c.2566C>Tp.R856C否chrX半合错义变异LPXL
55c.2318+1G>A否chrX半合剪接变异LPXL
58c.2343G>Ap.M781I否chrX半合错义变异LPXL
18SRD5A2c.16C>Tp.Q6*否chr2纯合无义变异LPAR类固醇5-α还原酶缺乏症
36c.282-2A>G否chr2纯合剪接变异LPAR
56CYP17A1c.297+2T>C否chr10纯合剪接变异LP`AR17,20裂解酶缺乏性先天性肾上腺皮质增生症
42NR5A1c.722G>Tp.Q258*是chr9杂合无义变异LPAD46,XY性反转3型
59SRYc.178G>Cp.V60L否chrY半合错义变异PYL46,XY性反转1型
), ArticleFig(id=1198630237895488304, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619423213978100, language=EN, label=Tab.4, caption=

Genetic characteristics of CNV in 46,XY DSD patients

, figureFileSmall=null, figureFileBig=null, tableContent=
患者编号基因染色体位置转录本编号氨基酸变化基因亚区遗传模式致病性分类相关疾病
9CYP21A2chr6：32009127-32010608NM_000500.7：EX10E DelEX10EARLP21-羟化酶缺乏性先天性肾上腺皮质增生症
29AKR1C2chr10：5037510-5037676NM_001354.5：EX9 DupEX9ARLP46,XY性反转8型
35AKR1C2chr10：5041391-5041469NM_001354.5：EX6 DelEX6ARLP46,XY性反转8型
41CBX2chr17：77752036-77752226NM_005189.2：EX1-EX2 DupEX1-EX2ARLP46,XY性反转5型
44NR5A1chr9：127253361-127255428NM_004959.4：EX5-EX6 DelEX5-EX6ADLP46,XX性反转4型
), ArticleFig(id=1198630237966791474, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619423213978100, language=CN, label=表4, caption=

46,XY DSD患者CNV遗传学特征

, figureFileSmall=null, figureFileBig=null, tableContent=
患者编号基因染色体位置转录本编号氨基酸变化基因亚区遗传模式致病性分类相关疾病
9CYP21A2chr6：32009127-32010608NM_000500.7：EX10E DelEX10EARLP21-羟化酶缺乏性先天性肾上腺皮质增生症
29AKR1C2chr10：5037510-5037676NM_001354.5：EX9 DupEX9ARLP46,XY性反转8型
35AKR1C2chr10：5041391-5041469NM_001354.5：EX6 DelEX6ARLP46,XY性反转8型
41CBX2chr17：77752036-77752226NM_005189.2：EX1-EX2 DupEX1-EX2ARLP46,XY性反转5型
44NR5A1chr9：127253361-127255428NM_004959.4：EX5-EX6 DelEX5-EX6ADLP46,XX性反转4型
), ArticleFig(id=1198630238046483251, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619423213978100, language=EN, label=Tab.5, caption=

Clinical phenotypes of patients with mutant sites

, figureFileSmall=null, figureFileBig=null, tableContent=
患者编号基因性别年龄(岁)临床表现
4AR女33双侧乳房发育正常；外阴大小阴唇发育正常，无阴毛。可见阴道口，但阴道为盲端
7AR女28月经未来潮
9CYP21A2女26原发不孕，性发育迟缓、原发性闭经、幼稚子宫
10AR女9DSD，双侧腹股沟触及睾丸
18SRD5A2女12乳房未发育，闭经
19AR女33双乳发育不佳，外阴呈女性，阴毛稀疏，双侧腹股沟未触及睾丸
20AR女3腹股沟内有隐睾
29AKR1C2女16原发性闭经
35AKR1C2女18原发性闭经
36SRD5A2女10无乳房发育，B超提示无子宫
37AR女1外生殖器性别模糊
41CBX2女17继发性闭经，乳房未发育
42NR5A1女19原发性闭经
43AR女22原发性闭经，外阴呈女性，可见阴道口，但阴道为盲端，双侧腹股沟未触及睾丸
44NR5A1女11无乳房发育
55AR女25原发性闭经，外阴幼女型，未见阴毛，未见宫颈，子宫触诊不清
56CYP17A1女22超声提示先天性无子宫、卵巢，乳房无发育、未触及乳核、阴蒂肥大、小阴唇少许色素沉着
58AR女23B超未探及卵巢和子宫
59SRY女35B超未见子宫、卵巢，乳房无发育，有阴毛和腋毛，外生殖器女性外观
), ArticleFig(id=1198630238121980725, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198619423213978100, language=CN, label=表5, caption=

携带突变位点患者的临床表型

, figureFileSmall=null, figureFileBig=null, tableContent=
患者编号基因性别年龄(岁)临床表现
4AR女33双侧乳房发育正常；外阴大小阴唇发育正常，无阴毛。可见阴道口，但阴道为盲端
7AR女28月经未来潮
9CYP21A2女26原发不孕，性发育迟缓、原发性闭经、幼稚子宫
10AR女9DSD，双侧腹股沟触及睾丸
18SRD5A2女12乳房未发育，闭经
19AR女33双乳发育不佳，外阴呈女性，阴毛稀疏，双侧腹股沟未触及睾丸
20AR女3腹股沟内有隐睾
29AKR1C2女16原发性闭经
35AKR1C2女18原发性闭经
36SRD5A2女10无乳房发育，B超提示无子宫
37AR女1外生殖器性别模糊
41CBX2女17继发性闭经，乳房未发育
42NR5A1女19原发性闭经
43AR女22原发性闭经，外阴呈女性，可见阴道口，但阴道为盲端，双侧腹股沟未触及睾丸
44NR5A1女11无乳房发育
55AR女25原发性闭经，外阴幼女型，未见阴毛，未见宫颈，子宫触诊不清
56CYP17A1女22超声提示先天性无子宫、卵巢，乳房无发育、未触及乳核、阴蒂肥大、小阴唇少许色素沉着
58AR女23B超未探及卵巢和子宫
59SRY女35B超未见子宫、卵巢，乳房无发育，有阴毛和腋毛，外生殖器女性外观
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全外显子组测序对性发育异常患者的分子遗传学病因分析
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吴柳娇 1 , 靳婵婵 2 , 朱姝 2 , 黄文明 2 , 叶建宏 2 , 吕涛 2 , 朱宝生 2 , 贺静 2, *
解放军医学杂志 | 临床研究 2024,49(5): 495-503
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解放军医学杂志 | 临床研究 2024, 49(5): 495-503
全外显子组测序对性发育异常患者的分子遗传学病因分析
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吴柳娇1, 靳婵婵2, 朱姝2, 黄文明2, 叶建宏2, 吕涛2, 朱宝生2, 贺静2, *
作者信息
  • 1昆明理工大学医学院，云南昆明 650500
  • 2云南省第一人民医院医学遗传科/国家卫生健康委西部孕前优生重点实验室，云南昆明 650500

    • 吴柳娇，硕士研究生，主要从事医学遗传学方面的研究

通讯作者:

贺静，E-mail：
Analysis on genetic etiology of disorders of sex development using whole exome sequencing
Liu-Jiao Wu1, Chan-Chan Jin2, Shu Zhu2, Wen-Ming Huang2, Jian-Hong Ye2, Tao Lyu2, Bao-Sheng Zhu2, Jing He2, *
Affiliations
  • 1Medical School , Kunming University of Science and Technology, Kunming, Yunnan 650500, China
  • 2Department of Medical Genetics, the First People's Hospital of Yunnan Province/Key Laboratory of National Health Commission for Pre-pregnancy Eugenics in Western China, Kunming, Yunnan 650500, China
出版时间: 2024-05-28 doi: 10.11855/j.issn.0577-7402.2548.2023.1227
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摘要
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目的 通过全外显子组测序(WES)技术分析性发育异常(DSD)患者的分子遗传学病因，以加深对DSD致病机制的认识。方法 收集2008年3月-2021年8月于云南省第一人民医院就诊的60例DSD患者的临床资料进行回顾性分析，并对其中1个先证者进行家系研究。提取所有患者的外周血基因组DNA进行WES测序分析，WES结果利用SAMtools软件、单核苷酸多态性(SNP)数据库、InDel数据库进行SNP和InDel检测；采用ExomeDepth进行外显子水平的拷贝数变异(CNV)检测；应用PolyPhen-2、Mutation taster、PyMol软件进行突变的有害性预测，并采用Sanger进行测序验证。结果 60例DSD患者中，22例为46,XX DSD，38例为46,XY DSD。22例46,XX DSD患者中14例存在SRY基因；在另外8例患者和其中1个先证者家系中，2例患者的NR5A1、PROKR2和ANOS1基因发生单核苷酸变异(SNV)，4例患者中的CYP21A2基因发生CNV，其中CYP21A2 EX1 Dup已有该变异的相关致病性报道，其余3个CNV为意义未明的变异，2例未检出与DSD相关的基因突变位点。38例46,XY DSD患者WES分析结果中，14例中检出了10个致病或疑似致病变异位点，包括SRY、AR、SRD5A2、CYP17A1、NR5A1等5个基因；5例中检出CYP21A2、AKR1C2、CBX2、NR5A1基因的5个疑似致病的CNV，其中3个微缺失，2个微重复。WES结果中NR5A1(c.722G>T、c.48C>G)、ANOS1 c.564A>T变异为首次报道的位点，在检出的CNV中，CYP21A2 EX1 Dup在相关数据库中有致病性的报道，其余未见报道。结论 WES技术的应用提高了对DSD的诊断能力，拓展了现有的DSD相关致病基因突变谱数据，丰富了对DSD致病机制的认识，可为开展遗传咨询提供帮助。

性发育异常  /  全外显子组测序  /  诊断  /  异质性

Objective To elucidate the molecular genetic etiology of patients with disorders of sex development (DSD) using whole exome sequencing (WES), thereby enhancing our understanding of the underlying mechanisms of sexual development abnormalities. Methods Retrospective analysis was conducted on clinical data of 60 DSD patients diagnosed in the First People's Hospital of Yunnan Province between March 2008 and August 2021, with an additional family study for one proband. Genomic DNA was extracted from patients for WES analysis. Single nucleotide polymorphism (SNP) and insertions/deletion (InDel) tests were identified using SAMtools software in conjunction with established SNP and InDel databases. Copy number variations (CNVs) at the exon level were detected using ExomeDepth, while the potential pathogenicity of mutations was predicted with PolyPhen-2, Mutation taster and PyMol software, with Sanger sequencing employed for confirmation. Results The study included 22 patients with 46,XX DSD and 38 with 46,XY DSD. Among the 46,XX DSD patients, the SRY gene was detected in 14 patients. In the remaining 8 patients and a proband's families, single nucleotide site variations (SNVs) of NR5A1, PROKR2 and ANOS1 genes were identified in 2 patients, and CNVs in CYP21A2 gene were found in 4 patients. The pathogenicity of CYP21A2 EX1 Dup has been previously reported, while the remaining 3 CNVs were of uncertain significance, and no DSD-related mutations were detected in 2 patients. In the WES analysis of 46,XY DSD patients, 10 pathogenic or likely pathogenic SNVs across 5 genes (SRY, AR, SRD5A2, CYP17A1, and NR5A1) were identified in 14 patients. Additionally, 5 likely pathogenic CNVs involving the CYP21A2, AKR1C2, CBX2, and NR5A1 genes were detected in 5 patients, comprising 3 deletions and 2 duplications. Novel SNVs in NR5A1 (c.722G>T, c.48C>G) and ANOS1 c.564A>T were identified, with no prior reports in relevant databases. The pathogenicity of CYP21A2 EX1 Dup is documented in related databases, while the remaining CNVs have not been previously reported. Conclusion The utilization of WES technology has enhanced the diagnostic potential for DSD, broadened the spectrum of known DSD-related gene mutations, and deepened our comprehension of DSD pathogenesis, offering valuable support for genetic counseling.

disorders of sex development  /  whole exome sequencing  /  diagnosis  /  heterogeneity
吴柳娇, 靳婵婵, 朱姝, 黄文明, 叶建宏, 吕涛, 朱宝生, 贺静. 全外显子组测序对性发育异常患者的分子遗传学病因分析. 解放军医学杂志, 2024 , 49 (5) : 495 -503 . DOI: 10.11855/j.issn.0577-7402.2548.2023.1227
Liu-Jiao Wu, Chan-Chan Jin, Shu Zhu, Wen-Ming Huang, Jian-Hong Ye, Tao Lyu, Bao-Sheng Zhu, Jing He. Analysis on genetic etiology of disorders of sex development using whole exome sequencing[J]. Medical Journal of Chinese People’s Liberation Army, 2024 , 49 (5) : 495 -503 . DOI: 10.11855/j.issn.0577-7402.2548.2023.1227
正文
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性发育异常(disorders of sex development，DSD)是指性腺或性别解剖结构不典型的先天性疾病[1]，涵盖内分泌及生殖系统的广泛表型异常。DSD分为性染色体DSD、46,XY DSD和46,XX DSD[2]，病因主要有染色体数量或结构异常、性腺或生殖器发育有关基因变异、性腺或肾上腺类固醇合成障碍、母体因素、生殖器发育的内分泌干扰因素或表观遗传变异等[3-4]。流行病学调查显示，DSD患病率为1/5000~1/4500[5]。DSD可产生与生殖器畸形、不孕不育、性腺恶变形成肿瘤等相关的问题，故早期诊断有助于为患者提供适当的治疗和长期的随访。由于DSD是一种非单一病因且临床表型复杂多样的疾病，对生殖器和生殖腺不明确的DSD患者进行诊断颇具挑战，且病因学诊断常常需要进行细胞遗传学检查结合临床表型、影像检查、生化检查、分子检查等，目前仍有约50%的DSD患者做完上述检查后仍未能获得准确的诊断。基因检测有助于提高DSD诊断的准确性。目前，绝大多数与疾病相关的基因位于外显子区，而外显子组序列仅占全基因组的1%左右，因此利用全外显子组测序(whole exome sequencing，WES)技术可直接发现与蛋白质功能变异相关的遗传变异，也能发现新的变异基因，可对近20%的罕见疾病进行基因诊断，已成为当前研究罕见综合征及复杂疾病的有效技术方法[6-7]。本研究应用WES技术对60例散发病例及1个DSD家系进行分析，探讨DSD的遗传学病因，旨在为明确DSD病因和预后提供指导。
1 资料与方法
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1.1 研究对象
收集2008年3月-2021年8月于云南省第一人民医院就诊的60例DSD患者的临床资料(包括相关的病史、临床表现、实验室检查和影像学检查结果)进行回顾性分析。此外，经患者知情同意后采集静脉血于-80 ℃保存待用，并针对其中的1例先证者进行家系研究，对其家系成员进行遗传咨询。本研究已获云南省第一人民医院医学伦理委员会审批(HLL2020-KY025)。
1.2 基因组DNA提取
采用西安天隆DNA提取试剂盒按操作流程提取外周血基因组DNA，Nano-Drop分光光度仪测量DNA浓度，吸光度A260/A280为1.8~2.0，采用Qubit定量仪测量DNA质量浓度，其中，浓度≥20 ng/μl为合格；<20 ng/μl时，浓度≥10 ng/μl可进行建库。
1.3 WES分析
将基因组DNA进行酶切打断形成150~300 bp的DNA片段，利用华大生物科技(武汉)有限公司的外显子组文库构建试剂盒进行片段选择、末端修复加“A”、接头连接纯化制备DNA文库，外显子组杂交捕获试剂盒进行文库的pooling、与探针进行杂交、外显子捕获，经PCR扩增后进行文库质检，采用MGISEQ-2000平台的标准流程进行测序。
1.4 生物信息学分析
原始数据采用FastQC对数据进行质量控制，过滤接头、N含量过多的片段，用BWA软件将所获得的序列与人类参考基因组进行比对，比对结果经SAMtools软件转换格式后利用Picard软件去除PCR重复的片段。利用人类已知的单核苷酸多态性(SNP)、插入缺失(InDel)标记(https://www.ncbi.nlm.nih.gov/)数据库，将上述比对结果使用GATK4软件进行SNP和InDel检测，并使用ExomeDepth进行外显子水平的拷贝数变异(CNV)检测。利用Annorvar软件将上述检测结果注释到Refseq千人基因(https://www.ncbi.nlm.nih.gov/refseq/)、EXAC(https://exac.broadinstitute.org/)、Esp6500(http://evs.gs.washington.edu/EVS/)、GnomAD(http://www.gnomad-sg.org/)、SIFT(https://sift.bii.a-star.edu.sg/)、Clinvar(https://www.ncbi.nlm.nih.gov/clinvar/)、OMIM(https://www.ncbi.nlm.nih.gov/omim/)等数据库进行突变的关联注释，并依据DSD为疾病背景寻找相关的变异基因及位点。利用PolyPhen-2、Mutation taster、PyMOL、AlphaFold等软件对突变的有害性进行预测分析，根据美国医学遗传学与基因组学会(American College of Medical Genetics and Genomics，ACMG)遗传变异分类标准与指南对变异进行致病性评估。
1.5 Sanger测序验证
通过PCR扩增和Sanger测序的方法对WES检出的基因突变位点序列进行验证，采用Primer5设计一代测序的引物，应用Chromas读取测序结果。
2 结果
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2.1 WES测序结果
2.1.1 46,XX DSD检测结果
在60例DSD患者中，22例为染色体核型46,XX，临床表型包括生殖器模糊、尿道下裂、隐睾、无精子症、不育等。22例中14例检出SRY基因。8例未检出SRY基因的患者进一步行WES测序，结果显示，2例检出3个基因的3个单核苷酸变异(single nucleotide variant，SNV)，分别为NR5A1 c.48C>G、PROKR2 c.253C>T、ANOS1 c.564A>T(表1)，其中PROKR2 c.253C>T已有该变异的致病性报道，NR5A1 c.48C>G、ANOS1 c.564A>T在相关的数据库中未见报道，经PolyPhen-2、Mutation taster预测分析，3个突变位点为有害突变；在4例患者中检出CYP21A2基因的5个CNV，均为微重复(表2)，其中CYP21A2 EX1 Dup在相关数据库中有致病性的报道，其余未见报道。
2.1.2 46,XY DSD检测结果
在38例46,XY DSD患者的WES检测结果中，19例检出致病基因，其中14例检出5个基因(SRY、AR、SRD5A2、CYP17A1、NR5A1)的10个致病或疑似致病的SNV(表3)，5例检出4个基因(CYP21A2、AKR1C2、CBX2、NR5A1)的5个疑似致病CNV(表4)。在检出的SNV中，9例为AR基因变异引起的DSD表型，2例为SRD5A2基因变异，3例中分别检出SRY、CYP17A1、NR5A1变异，其中NR5A1(c.722G>T)在Clinvar (https://www.ncbi.nlm.nih.gov/clinvar)、Genecards (https://www.genecards.org)、HGMD (https://www.hgmd.cf.ac.uk)等数据库中未见报道，NR5A1(c.722G>T)为无义突变，由于722位的G突变为T，导致第258位的谷氨酰胺的密码子突变为终止密码子，使多肽链合成提前终止。在检出的CNV中，包括3个缺失变异，2个重复变异，在相关数据库中均未见报道，5个CNV皆有可能引起蛋白截短或激活无义介导的mRNA降解，从而影响基因编码产物的功能。相关临床表型见表5。
2.2 先证者及其家系分析
2.2.1 46,XY DSD检测结果
将其中1例46,XX DSD先证者及其家系进行分析，结果如下：先证者71，男，染色体核型为46,XX，因性发育畸形、尿道下裂、睾丸异常就诊，WES测序显示该患者存在PROKR2 c.253C>T(p.R85C)、ANOS1 c.564A>T(p.K188N)突变，Sanger测序验证了上述基因的突变(图1A)，其中，PROKR2 c.253C>T(p.R85C)为杂合突变，第253位的C突变为T，导致精氨酸突变为半胱氨酸，为已知的突变位点，源于父亲；ANOS1 c.564A>T(p.K188N)为杂合突变，第564位的A突变为T，导致赖氨酸突变为天冬氨酸，在Clinvar(https://www.ncbi.nlm.nih.gov/clinvar)、Genecards(https://www.genecards.org)、HGMD(https://www.hgmd.cf.ac.uk)数据库中未找到该位点的突变信息，源于母亲。经生物信息学预测ANOS1 c.564A>T(p.K188N)突变对蛋白结构影响不大(图1B)。突变氨基酸与周围氨基酸残基的连接方式和连接的氢键并未发生改变，保守性分析提示该位点突变在不同物种间高度保守(图1C)。PolyPhen-2、Mutation taster等软件评估提示，ANOS1 c.564A>T(p.K188N)突变极有可能致病(图1D)，预测结果提示氨基酸序列发生变化及蛋白特征可能受到了影响。
3 讨论
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DSD患者的性腺分化程度不同，产生的临床表型错综复杂，且就诊年龄跨度大，而致病基因数百种，导致DSD的诊断率较低[5-6]。本研究采用的WES技术仅捕获和测序外显子和紧邻的内含子区域，该区域覆盖了基因组中约95%的RefSeq蛋白编码区，而目前80%~90%的致病变异发生在外显子及其邻近的内含子区域，因此，WES技术可对近20%的罕见疾病进行基因诊断，已成为当前研究罕见综合征及复杂疾病的有效方法[8]。WES技术最初用于识别单核苷酸变体，随着生物信息学工具的进步，基于WES测序数据进行CNV的检测已日益受到重视，临床上检测CNV的常用软件/算法已超过20种，本研究采用了ExomeDepth软件对WES检测数据进行CNV分析。Marchuk等[9]发现，利用ExomeDepth软件对WES数据进行CNV分析，对于高覆盖度区域的缺失型CNV检测敏感度可达89%，重复型CNV则为65%，本研究检测结果中，在4例46,XX DSD患者中检出CYP21A2基因的5个CNV，在5例患者中检出CYP21A2、AKR1C2、CBX2、NR5A1基因的5个CNV。此外，WES不仅可识别已知的DSD基因，还可发现新的DSD基因，本研究中发现的NR5A1(c.722G>T、c.48C>G)、ANOS1 c.564A>T基因的SNV在相关的数据库中未见报道，检测到的CNV中，CYP21A2 EX1 Dup在相关数据库中有致病性的报道，其余CNV未见报道。
46,XX DSD主要表现为性腺发育异常(卵睾型DSD、卵巢发育不良、睾丸型DSD)及雄激素过多。研究报道，约80%的46,XX核型有睾丸的DSD病例中，可由Y染色体性别决定区SRY基因易位来解释[10]。本研究22例46,XX DSD患者中有14例检出存在SRY基因突变，占总例数的63.6%，与文献[10]基本相符。其余8例经WES测序分析后，发现6例中存在与DSD相关的CYP21A2、NR5A1、PROKR2、ANOS1基因变异。在46,XX个体中，先天性肾上腺增生症(CAH)是一组常染色体隐性遗传病，由肾上腺参与胆固醇合成皮质醇的几种类固醇合成酶中的一种完全或部分缺乏引起，超过95%的CAH病例是由类固醇21-羟基酶缺乏引起的[11]。本研究4例表型分别为尿道下裂、不育和无精子症的46,XX DSD患者中检出了CYP21A2的5个CNV，其中，CYP21A2 EX1 Dup在相关数据库中有致病性的报道，提示该基因的变异可能是导致患者产生与DSD相关临床表型的原因，其余检测到的CNV还需进一步进行功能性验证。在1例临床表型为原发性闭经的患者中检出NR5A1 c.48C>G(p.C16W)变异，该变异在HGMD数据库中未见收录，REVEL软件预测值为0.783，提示该突变对NR5A1基因的功能有影响。NR5A1突变是原发性卵巢功能不全(primary ovarian insufficiency，POI)的遗传原因，表现为原发性或继发性闭经、不孕、雌激素不足和促性腺激素水平升高等[12]。PROKR2、ANOS1是卡尔曼综合征(KS)的致病基因，KS是以特发性低促性腺激素性性腺功能减退症为特征的疾病，患者性腺发育不全，临床表型差异大，主要表现为睾丸小、阴茎短小、不育等。2000年报道了1例同时携带PROKR2和ANOS1突变基因的KS散发病例，提示这两个基因变异在KS的发生中具有协同作用的可能性，此后，有关PROKR2基因联合其他KS相关突变基因的两个基因突变模式的报道层出不穷[13]。本研究检测出1例同时携带PROKR2和ANOS1基因突变的患者，提示了KS的双基因突变致病模式。检出的PROKR2基因c.253C>T(p.R85C)变异在HGMD数据库中收录为与疾病明确相关的变异(DM)，同一位置的其他氨基酸的改变p.Arg85His、p.Arg85Gly、p.Arg85Leu为HGMD收录的KS相关的变异；REVEL软件预测值为0.422，提示该突变对PROKR2基因功能的影响不明确；该变异在促性腺功能减退症的患者中被检出[14]。此外，相关的功能研究表明，该突变位点导致受体的G蛋白偶联受损[15]。ANOS1 c.564A>T(p.K188N)变异在相关数据库中未见报道，经生物信息学软件预测可能该变异导致患者产生相关临床表型。
46,XY DSD是一组表型高度异质性的疾病，涉及AR、NR5A1、MAP3K1、WT1、AMH、AMHR2、SRD5A2等数10个基因[16]。本研究46,XY DSD患者中检测出SRY、AR、SRD5A2、CYP21A2、CYP17A1、NR5A1、AKR1C2、CBX2等7个基因的突变，如图2所示，在胚胎发育的性别决定过程中SRY基因的表达启动了一系列导致睾丸器官发育的信号事件。如果SRY基因发生突变，可能导致46,XY DSD的发生[17]，本研究检出1例46,XY女性患者SRY基因c.178G>C(p.V60L)位点的错义突变，该患者女性生殖器外观，B超检查未探及子宫，乳房无发育，有阴毛和腋毛；Vilain等[18]报道了一个家系，先证者的染色体核型为46,XY，临床表型为性腺发育障碍，并检测出SRY c.178G>C(p.V60L)变异，变异位点遗传自父亲。有研究发现，SRY c.178G>C(p.V60L)为致病突变[19]，且功能研究表明，该突变破坏了靶基因的转录激活和抑制、亚细胞的定位、磷酸化、蛋白稳定性和Wnt/B-catenin信号传导等[20]。CBX2、NR5A1两个基因在性别决定阶段发挥促进SRY基因表达的作用，在睾丸的发育过程中，CBX2可通过阻止卵巢途径中的基因上调来促进睾丸的发育，目前的研究中，只有1例46,XY DSD报告携带CBX2致病变异[21]，因此，导致46,XY DSD的CBX2致病变异是非常罕见的。NR5A1编码类固醇生成因子1(SF-1)，后者可调节SRY、SOX9基因的表达，是肾上腺和性腺类固醇合成的关键调节因子，也是下丘脑-垂体-性腺轴的关键调节因子[22]，该基因突变导致的临床表型广泛，从完全女性化外表到不同程度的男性化，46,XY DSD中9%~10%与该基因的突变有关[23-24]。本研究在编号为42的患者中发现了NR5A1 c.722G>T的无义突变，第258位脯氨酸密码子内的突变导致终止密码子的形成，可能引起蛋白截短或无义介导的mRNA降解，从而影响基因编码蛋白产物的功能，该变异位点在相关数据库中未见报道。雄激素受体(androgen receptor，AR)蛋白通过结合睾酮和双氢睾酮促进细胞对雄激素做出反应，该基因的突变会使细胞对雄激素不同程度的不敏感，从而导致46,XY的雄激素不敏感综合征(AIS)患者出现男性特征的异常发育[25]。本研究46,XY DSD患者中最常见的是AR基因突变，占检出致病基因患者的47.3%；在检出的AR基因突变中，c.1846C>T、c.2567G>A、c.2566C>T、c.2343G>A、c.2318+1G>A为相关文献或数据库收录的疑似或致病变异；c.2318+1G>A变异为剪接变异，该变异导致了高度保守的供体剪接位点，进而发生异常剪接而导致AR基因编码蛋白产物的功能发生改变。SRD5A2、AKR1C2和CYP17A1是类固醇合成途径中的基因，SRD5A2编码5α还原酶，该酶催化睾酮转化为双氢睾酮，其缺失可导致46,XY核型患者存在广泛的男性化不足，在相关报道中该基因的突变与导致的临床表型(男性假两性畸形、生殖器模糊、隐睾、尿道下裂等)有关，与AIS存在表型重叠的现象[26]。本研究在1例原发性闭经患者中发现了该基因的c.16C>T、c.282-2A>G两个突变位点，均为纯合突变，其中c.16C>T为无义突变。CYP17A1是合成类固醇激素所必需的，该基因的变异会影响雄激素的生物合成，从而导致46,XY DSD。AKR1C2可还原3α-羟基类固醇脱氢酶的活性，AKR1C2在胎儿睾丸中大量表达，参与双氢睾酮合成的替代途径，该基因的缺陷会导致男性生殖器发育不完全[27]，本研究在2例原发性闭经患者中发现了AKR1C2的CNV。
综上所述，DSD患者的临床表型及遗传学病因具有高度异质性且不同人种间发病率不同，虽然其中一部分患者可得到准确的基因学诊断，但多数仍无法在分子水平找到病因。本研究利用WES技术对60例DSD患者进行了检测，其中55%的患者检出了基因的致病或疑似致病变异，同时首次报道了NR5A1(c.722G>T、c.48C>G)、ANOS1 (c.564A>T)的SNV，检出的CNV中除了CYP21A2 EX1 Dup在相关数据库中有致病性的相关报道，其余变异均未见报道，拓展了现有的DSD相关致病基因突变谱数据。目前，基于WES测序数据进行CNV的检测已日益引起重视，提高了诊断率，已成为研究复杂先天性疾病的有效方式，为展开遗传咨询提供了强大帮助。测序发现的结果可帮助临床医师更好地描述DSD表型，以改善临床管理，为患者及其家庭建立更好的早期诊疗和治疗干预线索。
基金
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  • 国家自然科学基金(81860030)
  • 云南省技术创新人才培养项目(2019HB071)
文献
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doi: 10.11855/j.issn.0577-7402.2548.2023.1227
  • 接收时间：2022-12-08
  • 首发时间：2025-11-21
  • 出版时间：2024-05-28
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  • 收稿日期：2022-12-08
  • 录用日期：2023-02-08
基金
National Natural Science Foundation of China(81860030)
国家自然科学基金(81860030)
Yunnan Provincial Technological Innovation Talent Training Project(2019HB071)
云南省技术创新人才培养项目(2019HB071)
作者信息
    1昆明理工大学医学院，云南昆明 650500
    2云南省第一人民医院医学遗传科/国家卫生健康委西部孕前优生重点实验室，云南昆明 650500

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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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