<i>AR</i> gene functional domains and their role in clinical severity in androgen insensitivity syndrome: a single-center cohort from Turkey

Introduction Androgen receptor (AR) gene mutations are a common cause of 46, XY disorders of sex development (DSD), resulting in varying degrees of androgen insensitivity. This study aims to comprehensively evaluate the clinical features, hormone profiles, and AR gene variants of patients diagnosed with Androgen Insensitivity Syndrome (AIS), and to analyze the distribution of these variants across different functional domains.Materials and methods This retrospective, single-center study analyzed 16 cases of 46, XY DSD, all of whom were found to have AR variants from a single tertiary center in Turkey. Patients were evaluated based on their complaints, hormonal measurements, clinical features, and genetic diagnoses. Patients were classified as having Complete, Partial, or Mild AIS. The variants were categorized based on their location within the functional domains: The Ligand Binding Domain (LBD) and the N-terminal Domain (NTD).Results Patients were classified as having CAIS (8/16), PAIS (6/16), MAIS (1/16), and suspected diagnosis (1/16). The most common clinical finding was cryptorchidism (11/16). Ten different AR variants were detected: eight missense (p.Pro392Ser, p.Ala749Val, p.Val890Met, p.Asp733Asn, p.Arg856His, p.Arg856Cys, p.Glu494Ala, and p.Glu710Lys), one nonsense (p.Lys659Ter), and with p.Lys659Ter, p.Glu494Ala and being novel. A CAIS associated with p.Pro392Ser has been reported, and intrafamily variability has been documented in variants such as p.Arg856His and p.Pro392Ser. Most variants (10/16 patients) localized to the LBD. Individuals harboring LBD variants demonstrated lower external genital scores and shorter phallus lengths compared to those with NTD variants. T/DHT ratio was available in 11 patients and did not yield false-positive AIS diagnoses. Marked intrafamilial phenotypic variability was observed.Conclusion This study expands the AR variant spectrum in AIS and represents one of the more comprehensively characterized cohorts from our country. While LBD variants were more often associated with severe phenotypes and NTD variants with milder presentations, marked phenotypic variability was observed. Nevertheless, considerable phenotypic variability, including marked intrafamilial heterogeneity, was evident. The T/DHT ratio provided supportive biochemical information but did not replace the need for molecular confirmation. Molecular confirmation remains essential, and multidisciplinary, patient-centered management is warranted.