Duplications of the Functional CYP21A2 Gene Are Primarily Restricted to Q318X Alleles: Evidence for a Founder Effect

Context: Rare haplotypes with Q318X mutations and duplicated CYP21A2 genes have been reported to occur in different populations to a varying extent. Discrimination between a normal (Q318X mutation on one of the duplicated CYP21A2 genes) and a congenital adrenal hyperplasia (CAH, Q318X mutation without duplicated functional gene) allele is of importance, particularly for prenatal diagnosis and the respective genetic counseling. Although methods to differentiate between such alleles have been published only recently, it remains unclear with which frequency Q318X mutations are associated with duplicated CYP21A2 genes and whether these haplotypes have a common ancestry. Subjects and Methods: Human leukocyte antigen (HLA) typing has been performed in 38 unrelated individuals and in 11 family members detected to carry a Q318X mutation in the course of CYP21 genotyping using sequence, multiplex ligation-dependent probe amplification, and Southern blot analyses. Results: The majority (n = 32, 84.2%) of the 38 unrelated individuals carrying the Q318X mutation had the trimodular RCCX haplotype, carrying the Q318X mutation on a duplicated CYP21A2 gene. Twenty-two individuals of these 32 (68.8%) were of the rare HLA-B*50-Cw*06 haplotype, suggesting a common ancestry of this haplotype. In five (13.2%) of the 38 subjects, the Q318X mutation was not associated with a duplicated CYP21A2 gene and thus represents a CAH allele. None of these five patients had the above mentioned HLA haplotype. Conclusion: The majority of individuals in whom Q318X mutations are detected carry a duplicated functional CYP21A2 gene and the rare HLA-B*50-Cw*06 haplotype. To avoid false positive genotyping, it is of utmost importance to be aware of the high frequency of duplicated CYP21A2-genes in association with Q318X-aberrations.