Genetic Findings in a Cohort of Patients with Androgen Insensitivity Syndrome

Abstract Background: Androgen insensitivity syndrome (AIS) is a rare X-linked recessive inherited disorder caused by mutations in AR, a gene encoding androgen receptor. The aim of this study was to expand genetic spectrum of AIS.Methods: We performed a retrospective study on consecutive patients diagnosed as AIS from 2010 to 2020 in a single tertiary center. Variant analysis of AR gene was performed by PCR-Sanger sequencing. The pathogenicity of novel variants was evaluated by dual-luciferase reporter assay and immunofluorescence of AR protein in vitro. Results: A total of 19 unrelated 46,XY patients were enrolled, 14 with complete insensitivity syndrome (CAIS) and 5 with partial insensitivity syndrome (PAIS). We identified 19 AR variants: 12 (63.2%) were missense variants and 7 variants (36.8%) resulted in premature stop codon. Eight AR variants were novel, including P15Afs*69, S258Efs*47, W435Gfs*44, C560F, C577W, C580Afs*46, K718X and V819G. Dual-luciferase reporter assay found residual transcription activity of approximately 1% in six novel variants, which may explain the CAIS phenotype. The AR mutant protein (V819G) showed transcription activity of 59%, consistent with mild clinical features in one PAIS patient. Interestingly, another AR mutant protein (K718X) related to CAIS showed increased transcription activity but impaired nuclear localization. Conclusions: We identified eight novel AR variants related to AIS. Both residual transcription activity of AR and nuclear localization of AR protein were associated with the severity of AIS.