Integrated In Silico, Population-Genomic and In Vitro Characterization of Three Rare CYP21A2 Missense Variants (p.A90V, p.L108Q and p.L318M) Resolves Their Role in Congenital Adrenal Hyperplasia by 21-Hydroxylase Deficiency

Background

Congenital Adrenal Hyperplasia (CAH) due to 21-hydroxylase deficiency is caused by biallelic pathogenic variants in CYP21A2. Although well-established genotype-phenotype correlations exist for the common pseudogene-derived alleles, next-generation sequencing increasingly identifies rare missense variants whose clinical significance is unknown, which hampers classification, counselling and the selection of patients for new targeted therapies.