Identification of the Underlying Androgen Receptor Defect in the Dallas Reifenstein Family

CONTEXT: The Dallas Reifenstein family — first described in 1965 — includes 14 known members with partial androgen insensitivity syndrome (PAIS). However, the underlying molecular defect was never identified. OBJECTIVE: To identify the underlying genetic defect for PAIS in the Dallas Reifenstein family. DESIGN: DNA was purified from scrotal skin fibroblasts, and whole exome sequencing was then performed in four affected men in the family. Additional family members — both affected and unaffected — were subsequently recruited to confirm segregation of the candidate mutations with the PAIS phenotype. PATIENTS: The affected men have PAIS with infertility associated with azoospermia, hypospadias, and gynecomastia. RESULTS: All four men harbored an intronic variant NC_000023.10:g.66788676A>C between exon 1 and exon 2 of the androgen receptor (AR) canonical transcript NM_000044 (complementary DNA position NM_000044: c.1616+22072A>C) predicted to cause an alternatively spliced AR transcript. Reverse transcription (RT) polymerase chain (PCR) experiments detected the predicted PCR product of the alternatively spliced AR transcript, and the mutation segregated with the PAIS phenotype in this family. The transcript includes the insertion of 185 nucleotides with a premature stop codon at chrX:66863131-66863133, likely resulting in a reduction in AR protein expression due to nonsense-mediated decay. CONCLUSIONS: An intronic AR mutation was identified in the Dallas Reifenstein family. The findings suggest that in cases of PAIS without identifiable AR mutations in coding regions, intronic AR mutations should be considered.