Next-Generation Sequencing Reveals Novel Genetic Variants (SRY, DMRT1, NR5A1, DHH, DHX37) in Adults With 46,XY DSD
Next-Generation Sequencing Reveals Novel Genetic Variants (SRY, DMRT1, NR5A1, DHH, DHX37) in Adults With 46,XY DSD
复制标题
DOI：
10.1210/js.2019-00306
复制
发表时间：
2019-12-01
影响因子：
4.1
通讯作者：
Achermann, John C.
中科院分区：
文献类型：
--
作者：
Buonocore, Federica;Clifford-Mobley, Oliver;Achermann, John C.
背景：人类性别发育的遗传基础正在慢慢被阐明，目前已有40种不同的性别发育差异(或障碍)的遗传原因被报道。然而，使用传统方法很难得到特定的诊断，特别是在生化数据有限的成年人中。目的：我们使用有针对性的下一代测序方法来分析没有特定分子诊断的个体的已知和候选DSD基因。参与者和设计：我们研究了52名参加单中心成人服务的成年46，XY女性，她们是400名更大的队列中的一部分。排除17β-羟基类固醇脱氢酶缺乏症3型、5a-还原酶缺乏症2型和雄激素不敏感综合征等经典病症。研究队列中有广泛的工作诊断为完全性性腺发育不全(CGD)(n=27)和部分男性化46，XY DSD(PvDSD)(n=25)，其中包括部分性腺发育不良和具有广泛的“部分雄激素不敏感综合征”标签的患者。对180个基因进行了定向测序。结果：总体而言，在52名个体中有16名(30.8%)发现了可能的遗传原因(22.2%的CGD，40.0%的pvDSD)。在CGD组中发现性别决定区Y(SRY；n=3)、双性和单抗相关转录因子1(DMRT1；n=1)、NR5A1/类固醇生成因子-1(SF-1)(n=1)和沙漠刺猬(DHH；n=1)；在pvDSD组中发现NR5A1(n=5)、DHH(n=1)和Deah-box Helicase 37(DHX37；n=4)。下一代测序方法是无价的，特别是在成人群体中或在诊断生物化学不可能的地方。
Context: The genetic basis of human sex development is slowly being elucidated, and >40 different genetic causes of differences (or disorders) of sex development (DSDs) have now been reported. However, reaching a specific diagnosis using traditional approaches can be difficult, especially in adults where limited biochemical data may be available.Objective: We used a targeted next-generation sequencing approach to analyze known and candidate genes for DSDs in individuals with no specific molecular diagnosis.Participants and Design: We studied 52 adult 46,XY women attending a single-center adult service, who were part of a larger cohort of 400 individuals. Classic conditions such as17 beta-hydroxysteroid dehydrogenase deficiency type 3, 5a-reductase deficiency type 2, and androgen insensitivity syndrome were excluded. The study cohort had broad working diagnoses of complete gonadal dysgenesis (CGD) (n = 27) and partially virilized 46,XY DSD (pvDSD) (n = 25), a group that included partial gonadal dysgenesis and those with a broad "partial androgen insensitivity syndrome" label. Targeted sequencing of 180 genes was undertaken.Results: Overall, a likely genetic cause was found in 16 of 52 (30.8%) individuals (22.2% CGD, 40.0% pvDSD). Pathogenic variants were found in sex-determining region Y (SRY; n = 3), doublesex and mab3-related transcription factor 1 (DMRT1; n = 1), NR5A1/steroidogenic factor-1 (SF-1) (n = 1), and desert hedgehog (DHH; n = 1) in the CGD group, and in NR5A1 (n = 5), DHH (n = 1), and DEAH-box helicase 37 (DHX37; n = 4) in the pvDSD group.Conclusions: Reaching a specific diagnosis can have clinical implications and provides insight into the role of these proteins in sex development. Next-generation sequencing approaches are invaluable, especially in adult populations or where diagnostic biochemistry is not possible.