Context: Although CYP21A2 de novo mutations are assumed to account for 1-2% of CAH- alleles, and CYP21-genotyping has been done worldwide, there are only a few well documented cases of CYP21A2 de novo mutations. The majority of these are deletions due to unequal crossingovers owing to misalignment of homologous chromosomes during meiosis. Whereas so far only heterozygous deletions of the CYP21A1P pseudogene were seen as premutations for de novo aberrations, the present report addresses such a predisposing role for parental duplicated CYP21A2 genes.

Subjects and Methods: As part of routine diagnostic procedures CYP21A-genotyping has been performed in two unrelated female CAH index patients and in their clinically asymptomatic parents and siblings.

Results: Both patients have inherited the paternal Intron2splice (IVS2) mutation and have harboured a de novo gene aberration (large deletion and I271N/Exon 4) on their maternal haplotype. Surprisingly, both mothers were carriers of rare duplicated CYP21A2 haplotypes carrying CAH-alleles, which were not detected in the daughters. Among 133 CAH-alleles, that were detected in patients and that could be traced to the respective family members by genotyping, these two de novo aberrations (representing 1.5% of 133 traced CAH-alleles) were the only ones identified.

Conclusion: Since both de novo CYP21A2 gene aberrations so far identified in our laboratory, occurred in the gametes of mothers carrying rare duplicated CYP21A2 haplotypes, we hypothesize that duplicated CYP21A2 genes could predispose for de novo mutations in the offspring, which is of relevance for prenatal CYP21-genotyping and genetic counseling.