Molecular Genetics of 21‐Hydroxylase Deficiency

Abstract Steroid 21‐hydroxylase deficiency (21OHD) accounts for approximately 95% of cases of congenital adrenal hyperplasia, one of the most common inherited metabolic disorders. It can be clinically classified into classic and nonclassic 21OHD. Classic 21OHD is associated with glucocorticoid deficiency and, in 46,XX patients, with disorder of sex development. Mineralocorticoid synthesis may also be significantly impaired in two‐thirds of patients, leading to life‐threatening salt‐wasting (SW) crises. Nonclassic 21OHD is milder and presents mainly with hyperandrogenism. 21OHD is caused by mutations in the CYP21A2 gene. The vast majority of CYP21A2 mutations are a result of unequal crossing overs and gene conversions with its highly homologous pseudogene, CYP21A1P . Molecular genetic analysis is challenging and requires the combination of different methods to detect gene deletions, chimeric genes, gene duplications and point mutations. An overall good genotype–phenotype correlation exists for the SW phenotype. Therefore, molecular diagnosis of 21OHD complements clinical diagnosis and allows for clinical and genetic counselling. Key Concepts: Steroid 21‐hydroxylase deficiency (21OHD) is an autosomal recessive disorder caused by mutations in the CYP21A2 gene and represents the most common form of congenital adrenal hyperplasia. A good genotype–phenotype correlation exists for the mineralocorticoid deficiency phenotype. Although a trend exists, the severity of 46,XX disorder of sex development as well as of other hyperandrogenic signs and symptoms correlates less strongly with the CYP21A2 genotype. Common pseudogene‐derived mutations account for the majority of 21OHD disease‐causing alleles; these include gene deletions, chimeric genes, seven single point mutations, an 8 base‐pair deletion and a cluster of three point mutations. Molecular genetic analysis of the CYP21A2 gene is challenging due to the high‐sequence homology with its pseudogene ( CYP21A1P ), the high rate of large rearrangements with different break points, and the presence of complex alleles carrying various mutations. Some less common mutations are highly prevalent in specific populations due to founder effects. These should be considered in the genetic diagnosis of 21OHD when only screening for otherwise common CYP21A2 mutations. CYP21A2 gene duplications should be considered in carriers of the p.Gln318X mutation to provide the correct molecular genetic diagnosis. Molecular genetic diagnosis is essential to provide the correct diagnosis and allows for appropriate clinical and genetic counselling.