Abstract：
This study describes the clinical, biochemical, and molecular characteristics of Indian children with 46,XY DSD and suspected androgen insensitivity syndrome (AIS). Fifty children (median age 3.0 years, range 0-16.5 years) with 46,XY DSD and a suspected diagnosis of AIS were enrolled. Sanger sequencing was performed to identify pathogenic variants in the androgen receptor (AR) gene and to study genotype-phenotype correlations. All 5 (100%) patients with CAIS and 14/45 (31%) patients with PAIS had pathogenic/likely pathogenic variants in the AR gene (overall, 14 different variants in 19 patients; 38.8%). There was no significant difference in clinical (cryptorchidism, hypospadias, or external masculinizing score) or biochemical parameters (gonadotropins and testosterone) between patients with or without pathogenic variants. However, patients with AIS were more likely to have a positive family history, be assigned female gender at birth, and present with gynaecomastia at puberty. Three novel pathogenic/likely pathogenic variants, including one splice donor site variant c.2318+1G>A, one frameshift variant p.H790Lfs*40, and one missense variant p.G821E, were identified in 3 patients with CAIS. The missense variant p.G821E was predicted as deleterious, damaging, disease-causing, and likely functionally inactive by in silico analysis and protein modelling study. Two previously not reported pathogenic/likely pathogenic variants, including p.R386H and p.G396R, were identified in patients with PAIS. This study contributes in expanding the spectrum of pathogenic variants in the AR gene in patients with AIS. Only 31% patients with a provisional diagnosis of PAIS had pathogenic variants in the AR gene, suggesting other possible mechanisms or candidate genes may be responsible for such a phenotypic presentation.
摘要：
这项研究描述了临床，生物化学，和46，XYDSD和可疑雄激素不敏感综合征（AIS）的印度儿童的分子特征。50名儿童（平均年龄3.0岁，范围0-16.5年），46，XYDSD和怀疑诊断为AIS。进行Sanger测序以鉴定雄激素受体（AR）基因中的致病变体并研究基因型-表型相关性。所有5例（100％）CAIS患者和14/45例（31％）PAIS患者在AR基因中具有致病性/可能的致病性变异（总体，19例患者中有14种不同的变异；38.8%）。临床上没有显着差异（隐睾，尿道下裂,或外部男性化评分）或有或没有致病变异的患者之间的生化参数（促性腺激素和睾丸激素）。然而,AIS患者更有可能有积极的家族史，出生时被指定为女性，并在青春期出现妇科乳房发育症。三种新的致病性/可能的致病性变体，包括一个剪接供体位点变异体c.2318+1G>A,一个移码变体p.H790Lfs*40，一个错觉变体p.G821E，在3例CAIS患者中发现。错义变体p.G821E被预测为有害的，破坏性,引起疾病,通过计算机模拟分析和蛋白质建模研究，可能功能不活跃。两个以前未报告的致病性/可能的致病性变异，包括p.R386H和p.G396R，在PAIS患者中发现。这项研究有助于扩大AIS患者AR基因中致病变异的范围。只有31%的暂时诊断为PAIS的患者有AR基因的致病变异，提示其他可能的机制或候选基因可能是导致这种表型呈现的原因。
