A novel breakpoint deletion within a CAG repeat causes complete androgen insensitivity syndrome: Report of its segregation in a large Czech family

BACKGROUND: Complete androgen insensitivity syndrome (CAIS) is one of the most prevalent conditions of disorders/differences of sex development (DSD), with an X-linked recessive inheritance. A hemizygous pathogenic variant in the AR gene causes the condition. CASE REPORT: We present a five-generation Czech family with several CAIS-positive relatives. The proband is a 27-year-old female patient with a 46,XY karyotype, who exhibits the typical CAIS phenotype. This includes female external genitalia, the absence of uterus, a blind-ending vagina, undescended testes, and almost missing axillary and pubic hair. METHODS AND RESULTS: We identified a novel pathogenic, hemizygous NM_000044.4(AR):c.-66_220del p.? variant using Sanger DNA sequencing with specifically designed primers. This AR deletion was 286 bp in length and initiated in the 5'-UTR, terminating within the polymorphic CAG repeats in exon 1 of the AR gene. The AR variant removed the original initiation codon ATG, resulting in a shortened AR transcript with an unknown effect on the translation. CONCLUSION: We describe a unique AR deletion identified in a 46,XY female patient with CAIS. The variant segregates in the large CAIS family; it was detected in five affected relatives, while the four remaining family members were asymptomatic carriers.