Work

Accurate diagnosis of congenital adrenal hyperplasia due to CYP21A2 variants requires promoter analysis

Year: 2025

Type: article

Abstract: OBJECTIVE: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is an autosomal recessive disease mostly caused by compound heterozygous pathogenic CYP21A2 variants. CYP21A2 promoter analysis is frequently not included in routine diagnostics, but could explain discrepancies in the usually good genotype-phenotype correlation. Here we investigate frequency and type of CYP21A2 promoter variants and their influence on 21-OHD phenotype. DESIGN: Observational cohort study in a tertiary referral center and accredited genetic laboratory. METHODS: CYP21A2 genotyping including promoter analysis was performed and clinical/biochemical parameters were retrospectively collected in 1279 individuals undergoing routine diagnostic CYP21A2 genotyping. RESULTS: We detected promoter variants in 89 individuals (7.0%). Of 207 patients with 21-OHD, 12.1% had promoter variants. A large conversion including the promoter (c.-126C>T, c.-113G>A, c.-110T>C, c.-103A>G) and p.(Pro31Leu) in exon 1 was found in 21 patients and led to a mostly simply virilizing phenotype when occurring in trans with another classic allele. Promoter variants were observed in CAH patients with only 1 known pathogenic variant (n = 4) and in clinically unaffected individuals with no other CYP21A2 variant (n = 6); conventional sequencing without the promoter region would not have suggested CAH or 21-OHD carrier status in these individuals (n = 10). CONCLUSIONS: Non-benign promoter variants occur frequently in individuals with 21-OHD and clinically unaffected carriers. Promoter variants can aggravate clinical presentation in 21-OHD and can explain cases with discrepant genotype and phenotype. Inclusion of CYP21A2 promoter analysis in diagnostic procedures can improve accuracy of diagnosis, management and genetic counseling in patients with 21-OHD and their families.

Source: European Journal of Endocrinology

DOI: 10.1093/ejendo/lvaf217