背景:46,XY差异/性发育障碍(DSD)的特征是广泛的表型范围,从典型的女性到男性,外生殖器未充分。或更罕见的睾丸消退与典型的男性表型。尽管DSD的基因诊断取得了进展,大多数46,XYDSD病例仍为特发性。
方法:为了确定46,XYDSD的遗传原因,我们研究了165名突尼斯血统的患者,谁提出了广泛的DSD表型。核型分析,候选基因测序,进行全外显子组测序(WES)。
结果:细胞遗传学异常,包括高频率的性染色体异常(85.4%),在30.9%(51/165)的队列中解释了表型。候选基因的Sanger测序在46,XY性腺发育不全患者的SRY基因中鉴定出一种新的致病变异。对44例46,XYDSD患者的外显子组筛查显示,38.6%(17/44)的患者具有致病性或可能的致病性变异。
结论:在AR中发现了罕见或新的致病变异,SRD5A2、ZNRF3、SOX8、SOX9和HHAT基因。总体而言,我们的数据表明,在46,XYDSD组中,遗传诊断率为41.2%(68/165)。
BACKGROUND: Forty-six ,XY Differences/Disorders of Sex Development (DSD) are characterized by a broad phenotypic spectrum ranging from typical female to male with undervirilized external genitalia, or more rarely testicular regression with a typical male phenotype. Despite progress in the genetic diagnosis of DSD, most 46,XY DSD cases remain idiopathic.
METHODS: To determine the genetic causes of 46,XY DSD, we studied 165 patients of Tunisian ancestry, who presented a wide range of DSD phenotypes. Karyotyping, candidate gene sequencing, and whole-exome sequencing (WES) were performed.
RESULTS: Cytogenetic abnormalities, including a high frequency of sex chromosomal anomalies (85.4%), explained the phenotype in 30.9% (51/165) of the cohort. Sanger sequencing of candidate genes identified a novel pathogenic variant in the SRY gene in a patient with 46,XY gonadal dysgenesis. An exome screen of a sub-group of 44 patients with 46,XY DSD revealed pathogenic or likely pathogenic variants in 38.6% (17/44) of patients.
CONCLUSIONS: Rare or novel pathogenic variants were identified in the AR, SRD5A2, ZNRF3, SOX8, SOX9 and HHAT genes. Overall our data indicate a genetic diagnosis rate of 41.2% (68/165) in the group of 46,XY DSD.