Abstract：
OBJECTIVE: 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).
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
目的：46,XY性发育障碍（46,XYDSD）的病因复杂，研究表明，不同系列的46、XYDSD患者具有不同的遗传谱。在这项研究中,我们旨在通过全外显子组测序（WES）研究中国系列46,XYDSD患者的潜在遗传病因。
方法：北京协和医院收集了70例46,XYDSD患者（北京，中国）。评估了详细的临床特征，收集外周血进行WES，以寻找与46，XYDSD相关的基因的罕见变异（RV）。根据美国医学遗传学和基因组学学院（ACMG）指南注释了RV的临床意义。
结果：在56例46，XYDSD患者中，共鉴定出来自9个基因的57个RV，其中包括21种新型房车和36种复发性房车。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个变体被定义为不确定意义的变体（VUS）。在该系列的64.3%(45/70)的患者中鉴定出P或LP变异。三十九，14,四个房车参与了雄激素的合成和作用过程，睾丸决定和发育过程，和综合征46，XYDSD，分别。引起46，XYDSD最常见的三个基因是AR，SRD5A2和NR5A1。近年来发现7例患者携带有46,XYDSD致病基因的RV,即DHX37在四名患者中，两名患者的MYRF和一名患者的PPP2R3C。
结论：我们确定了9个基因的21个新RV，扩展了46，XYDSD致病变异的遗传谱。我们的研究表明，60%的患者是由AR引起的，SRD5A2或NR5A1P/LP变体。因此,可以首先对这三个基因进行PCR扩增和Sanger测序，以鉴定患者的病因。对于那些尚未发现致病变异的患者，全外显子组测序可能有助于确定病因.本文受版权保护。保留所有权利。
方法：北京协和医院收集了70例46,XYDSD患者（北京，中国）。评估了详细的临床特征，收集外周血进行WES，以寻找与46，XYDSD相关的基因的罕见变异（RV）。根据美国医学遗传学和基因组学学院（ACMG）指南注释了RV的临床意义。
结果：在56例46，XYDSD患者中，共鉴定出来自9个基因的57个RV，其中包括21种新型房车和36种复发性房车。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个变体被定义为不确定意义的变体（VUS）。在该系列的64.3%(45/70)的患者中鉴定出P或LP变异。三十九，14,四个房车参与了雄激素的合成和作用过程，睾丸决定和发育过程，和综合征46，XYDSD，分别。引起46，XYDSD最常见的三个基因是AR，SRD5A2和NR5A1。近年来发现7例患者携带有46,XYDSD致病基因的RV,即DHX37在四名患者中，两名患者的MYRF和一名患者的PPP2R3C。
结论：我们确定了9个基因的21个新RV，扩展了46，XYDSD致病变异的遗传谱。我们的研究表明，60%的患者是由AR引起的，SRD5A2或NR5A1P/LP变体。因此,可以首先对这三个基因进行PCR扩增和Sanger测序，以鉴定患者的病因。对于那些尚未发现致病变异的患者，全外显子组测序可能有助于确定病因.本文受版权保护。保留所有权利。
