GENETIC-COUNSELING IN COMPLETE ANDROGEN INSENSITIVITY SYNDROME - TRINUCLEOTIDE REPEAT POLYMORPHISMS, SINGLE-STRAND CONFORMATION POLYMORPHISM AND DIRECT-DETECTION OF 2 NOVEL MUTATIONS IN THE ANDROGEN RECEPTOR GENE

OBJECTIVE Androgen insensitivity syndrome is a disorder of male sexual development which results in varying degrees of undervirilization in 46XY individuals with functional testes. In the most severe form, comp lete androgen insensitivity syndrome (CAIS), patients have a normal fe male appearance. Although CAIS is not life-threatening, affected indiv iduals are infertile and require counselling, gonadectomy, hormone the rapy, and sometimes vaginoplasty. Many families therefore request gene tic counselling. Defects in the androgen receptor gene account for mos t if not all cases of CAIS. The purpose of this study was to evaluate the use of the polyglutamine and polyglycine trinucleotide repeat poly morphisms in the first exon of the androgen receptor gene for carrier status determination in three CAIS families. In two of these families novel mutations in the androgen receptor gene were subsequently identi fied which allowed confirmation of carrier status and also a prenatal diagnosis to be made in one family. PATIENTS Three CAIS families were studied. The index cases all presented with a clinical phenotype typic al of CAIS. MEASUREMENTS Family members were typed initially for the p olyglutamine repeat. In one family this was not informative and the po lyglycine repeat was therefore studied. In this and one further family , the androgen receptor gene was sequenced to identify the mutation ca using the CAIS. RESULTS On the basis of information from trinucleotide repeat analysis carrier status could be assessed in each family. In o ne family, evidence for somatic instability of the polyglutamine repea t was found. In the same family, a novel mutation in the androgen rece ptor gene, which substituted valine for leucine 881, was identified. O ther family members were subsequently typed for the mutation and a pre natal diagnosis was performed. A novel mutation was also identified in a second family substituting the glycine codon at position 371 with a stop codon. Other family members were typed for this mutation. CONCLU SIONS Both the polyglutamine and polyglycine repeat polymorphisms are useful for the genetic counselling of complete androgen insensitivity syndrome families. In some cases, however, where the family history is limited, more precise information can be provided only once the andro gen receptor mutation causing the complete androgen insensitivity synd rome has been identified.