Department of Endocrinology, NHC Key laboratory of Endocrinology (Peking Union Medical College Hospital), Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.
State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.
Andrology. 2024 Jan;12(1):98-108. doi: 10.1111/andr.13446. Epub 2023 May 19.
The etiology of 46, XY disorders of sex development (46, XY DSD) is complex, and studies have shown that different series of patients with 46, XY DSD has different genetic spectrum. In this study, we aimed to investigate the underlying genetic etiology in a Chinese series of patients with 46, XY DSD by whole exome sequencing (WES).
Seventy patients with 46, XY DSD were enrolled from the Peking Union Medical College Hospital (Beijing, China). The detailed clinical characteristics were evaluated, and peripheral blood was collected for WES to find the patients' rare variants (RVs) of genes related to 46, XY DSD. The clinical significance of the RVs was annotated according to American College of Medical Genetics and Genomics (ACMG) guidelines.
A total of 57 RVs from nine genes were identified in 56 patients with 46, XY DSD, which include 21 novel RVs and 36 recurrent RVs. Based on the American ACMG guidelines, 43 variants were classified as pathogenic(P) or likely pathogenic (LP) variants and 14 variants were defined as variants of uncertain significance (VUS). P or LP variants were identified in 64.3% (45/70) patients of the series. Thirty-nine, 14, and 4 RVs were involved in the process of androgen synthesis and action, testicular determination and developmental process, and syndromic 46, XY DSD, respectively. The top three genes most frequently affected to cause 46, XY DSD were AR, SRD5A2, and NR5A1. Seven patients were found harboring RVs of the 46, XY DSD pathogenic genes identified in recent years, namely DHX37 in four patients, MYRF in two patients, and PPP2R3C in one patient.
We identified 21 novel RVs of nine genes, which extended the genetic spectrum of 46, XY DSD pathogenic variants. Our study showed that 60% of the patients were caused by AR, SRD5A2 or NR5A1 P/LP variants. Therefore, polymerase chain reaction (PCR) amplification and Sanger sequencing of these three genes could be performed first to identify the pathogeny of the patients. For those patients whose pathogenic variants had not been found, whole-exome sequencing could be helpful in determining the etiology.
46，XY 性发育障碍（46，XY DSD）的病因复杂，研究表明，不同系列的 46，XY DSD 患者具有不同的遗传谱。本研究旨在通过全外显子组测序（WES）研究中国 46，XY DSD 患者的潜在遗传病因。
从北京协和医院（北京，中国）招募了 70 名 46，XY DSD 患者。评估详细的临床特征，并采集外周血进行 WES 以寻找与 46，XY DSD 相关的基因的患者罕见变异（RVs）。根据美国医学遗传学与基因组学学院（ACMG）指南对 RVs 的临床意义进行注释。
在 56 名 46，XY DSD 患者中发现了 9 个基因的 57 个 RVs，包括 21 个新的 RVs 和 36 个重复 RVs。根据美国 ACMG 指南，43 个变体被分类为致病性（P）或可能致病性（LP）变体，14 个变体被定义为意义不确定的变体（VUS）。该系列中 64.3%（45/70）的患者存在 P 或 LP 变体。39、14 和 4 个 RVs 分别涉及雄激素合成和作用、睾丸决定和发育过程以及综合征性 46，XY DSD。受影响导致 46，XY DSD 的三个最常见的基因是 AR、SRD5A2 和 NR5A1。发现 7 名患者携带最近发现的 46，XY DSD 致病基因的 RVs，即 4 名患者的 DHX37、2 名患者的 MYRF 和 1 名患者的 PPP2R3C。
我们鉴定了 9 个基因的 21 个新的 RVs，扩展了 46，XY DSD 致病变异的遗传谱。我们的研究表明，60%的患者是由 AR、SRD5A2 或 NR5A1 P/LP 变体引起的。因此，首先可以对这些三个基因进行聚合酶链反应（PCR）扩增和 Sanger 测序以确定患者的病因。对于尚未发现致病变体的患者，全外显子组测序有助于确定病因。
