CAG trinucleotide repeats in the androgen receptor gene of infertile men exhibit stable inheritance in female offspring conceived after ICSI

The androgen receptor (AR) gene is located on the X chromosome and contains a polymorphic CAG tract. CAG repeat expansions in the AR have been associa ted with male infertility and the neuromuscular disease, spinal bulbar musc ular atrophy (SBMA), Based on Mendelian inheritance patterns, moderate CAG expansions in infertile men treated by intracytoplasmic sperm injection (IC SI) would be vertically transmitted to female offspring. Should further elo ngation of the repeat region occur in the male germline, it is conceivable that longer expansions could also be transmitted by ICSI and may lead to an increased incidence of male infertility and SBMA in succeeding generations . To determine the degree of stability of the paternal AR CAG tract followi ng ICSI, we compared the CAG repeat number in the AR alleles of 92 men pres enting for ICSI and their 99 ICSI-conceived daughters. CAG repeat lengths i n the AR alleles were determined by fluorescent polymerase chain reaction a nd Genescan analysis of amplification products separated on DNA sequencing gels. In the vast majority of cases (95 out of 99), we found that the AR CA G tracts ranging in size from 15-28 repeats exhibited stable inheritance in female offspring. However, in the remaining father-daughter pairs, there w as a discordance in the expected inheritance pattern with evidence for both CAG expansion (20-->24; 22-->23) and contraction (26-->18 or 22) of the pa ternal AR allele, The detection of a low frequency of CAG mutation in pater nal AR alleles following ICSI would be consistent with gonadal mosaicism or iginating from meiotic DNA replication errors. These findings in a typical group of infertile men undergoing ICSI for a variety of indications tend to alleviate concerns that: ICSI may promote the transmission of AR alleles w ith expanded CAG tracts and suggest that the risk of SBMA in second generat ion sons would be extremely low.