Molecular spectrum of androgen receptor gene alterations in Belgian patients

Alterations throughout the androgen receptor (AR) gene influence male reproductive development and
function and are associated with androgen insensitivity syndrome (AIS), a disease with a prominent
genotypic-phenotypic heterogeneity.
We determined the AR gene sequence in 21 patients. Ten patients were suspicious of AIS. 4/6 with
known 46,XY karyotype had complete AIS (CAIS) and 1/6 had premature amenorrhea. The presence of
an Y-chromosome was confirmed in 2 patients by AR-MLPA, whereas karyotypes remained unknown for
2 AIS patients.
Three nonsense mutations were discovered at codons 353, 829 and 831 respectively, and a 4bp
duplication c.2227_2230dupATGG were found to induce a premature stopcodon at codon 769. Two
missense mutations at codon 700 and 860 were detected within the AR ligand binding domain.
Suspicion of AR-gene or -exon deletion in 2 patients, was corroborated by AR-MLPA, demonstrating the
importance of confirmation methodology. For the remaining 6 patients (few clinical and/or karyotype
information was available and) no AR-alterations were found. Carrier status was confirmed in 5
investigated relatives of some of the index cases.
Our study has revealed a number of previously undescribed amino acid alterations presumingly causing
impairment of the AR protein function.
Our findings demonstrate that AR sequencing and MLPA are important tools to support the clinical
diagnosis and counseling of AIS. Moreover, the AIS genetic testing may be used for prenatal diagnosis
and pre-implantation genetic diagnosis, for which the CAG-repeat in exon 1 can be used as marker.