UNIPARENTAL DISOMY FOR CHROMOSOME-6 RESULTS IN STEROID 21-HYDROXYLASEDEFICIENCY - EVIDENCE OF DIFFERENT GENETIC MECHANISMS INVOLVED IN THEPRODUCTION OF THE DISEASE

Congenital adrenal hyperplasia (CAH) is an inherited recessive disorde r of adrenal steroidogenesis caused by mutations in the steroid 21-hyd roxylase gene (CYP21) in more than 90% of affected patients. The CYP21 gene is located within the HLA complex locus on chromosome 6 (6p21.3) . During a molecular characterisation study of a group of 47 Mexican f amilies with 21-hydroxylase deficiency, we identified nine in which th e mutation or mutations found in the patient did not appear to origina te from one of the parents. Through DNA fingerprinting, paternity was established in all nine families with a probability of non-paternity i n the range of 10(-19) to 10(-23). Among these families, we identified one patient with exclusive paternal inheritance of all eight markers tested on chromosome 6p, despite normal maternal and paternal contribu tions for eight additional markers on three different chromosomes. me did not identify duplication of paternal information for markers in th e 6q region, consistent with lack of expression of transient neonatal diabetes owing to genomic imprinting in this patient. Our results subs tantiate evidence for the existence of different genetic mechanisms in volved in the expression of this recessive condition in a substantial portion (similar to 19%) of affected Mexican families. In addition to the identification of a patient with paternal uniparental disomy, the occurrence of germline mutations may explain the unusual pattern of se gregation in the majority of the remaining eight families.