Molecular genetics of 21-hydroxylase deficiency

More than 95% of all cases of congenital adrenal hyperplasia are caused by deficiency of steroid 21-hydroxylase, an enzyme encoded by the CYP21A2 gene. The severity of the clinical symptoms varies according to the level of residual 21-hydroxylase activity. The CYP21A2 gene is located in the HLA class III region, as a component of so called RCCX modules containing homologous genes repeated in tandem. Misalignment followed by unequal crossing over as well as gene conversion events result in a high degree of variation in gene copy number as well as gene sequence in this genomic region. The presence of a highly homologous pseudogene, CYP21A1P, forms the basis for the relatively high incidence of 21- hydroxylase deficiency as deleterious sequences can be transferred from CYP21A1P to CYP21A2. Despite the complexity of the locus, safe approaches for genotyping are established, and genotype phenotype relationships have been documented making genotyping a valuable complement to biochemical investigations in the diagnostics of 21-hydroxylase deficiency. This is of particular importance in relation to family investigations and neonatal screening.