Androgen insensitivity and the evolving genetic heterogeneity

Abstract

Androgen Insensitivity Syndrome (AIS) is a 46,XY difference of sex development (DSD) classically caused by mutations in the androgen receptor (AR) gene, leading to variable androgen resistance and a broad phenotypic spectrum traditionally classified as complete, partial, or mild. Phenotypic variability can occur even with identical AR mutations, particularly those within the ligand-binding domain of the AR. Emerging evidence implicates non-coding regulatory variants, deep intronic mutations, AR co-regulator dysfunction, and oligogenic inheritance in the aetiology of AIS. The molecular diagnostic workflow should incorporate either targeted AR sequencing or whole-exome sequencing, depending on the clinical context. Biochemical and functional assays remain clinically useful, especially when AR variants are not detected or when variants of unknown significance (VUS) are identified. Advances in patient-derived hiPSC models and testicular organoids provide new insights into AR function and therapeutic strategies. Expanding genomic and epigenetic research will refine diagnostic accuracy, and personalized care, ultimately optimizing patient outcomes in AIS.