Androgen receptor CAG_n repeat length influences phenotype of 47,XXY (Klinefelter) syndrome

Context: Klinefelter syndrome (KS; 47,XXY karyotype and variants) is characterized by tall stature and testicular failure, with marked variation in severity of the phenotype. Previous studies have proposed that genetic factors including mosaicism, parental origin of the supernumerary X-chromosome, skewed X inactivation, and androgen receptor (AR) polyglutamine repeat length may contribute to phenotypic variability in KS. Objective: The objective of this study was to investigate the roles of these genetic factors in the variability of the KS phenotype. Design: This was a cross-sectional study. Setting: The study was performed at a pediatric endocrinology referral clinic. Patients: Thirty-five KS boys and men, aged 0.1-39 yr, were studied. Interventions: There were no interventions. Main Outcome Measures: Auxological measurements, biological indices of testicular function, and clinical assessment of muscle tone were the main outcome measures. Genetic studies included karyotyping to detect mosaicism, genotyping of microsatellite markers to determine parental origin of the supernumerary X-chromosome, and genotyping and methylation studies to measure AR polyglutamine (AR CAG_n) repeat length and X inactivation ratio. Results: The only genetic factor that significantly influenced the KS phenotype was the AR CAG_n repeat length, which was inversely correlated with penile length, a biological indicator of early androgen action. Mosaicism, imprinting, and skewed X inactivation did not account for the variability of the KS phenotype. Conclusions: Normal genetic variation in the AR coding sequence may be clinically significant in the setting of early testicular failure and subnormal circulating testosterone levels, as occur in KS.