Accurate diagnosis of congenital adrenal hyperplasia due to CYP21A2 variants requires promoter analysis
Authors' conclusion
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.
Study context
- Population
- Individuals undergoing routine diagnostic CYP21A2 genotyping including promoter analysis, tertiary referral center
- Participants
- 1,279 individuals
- Outcome
- Frequency and type of CYP21A2 promoter variants and their influence on 21-OHD phenotype
Methodological detailsretrospective clinical/biochemical data collection, tertiary referral center and accredited genetic laboratory
- Retrospective clinical/biochemical data collection
- Tertiary referral center and accredited genetic laboratory
Main finding
As reported in the abstract
CYP21A2 promoter variants
- Individuals with promoter variants
- 89 (7.0%)
- Patients with 21-OHD (n = 207) with promoter variants
- 12.1%
- Large conversion incl. promoter (c.-126C>T, c.-113G>A, c.-110T>C, c.-103A>G) and p.(Pro31Leu) in exon 1; mostly simply virilizing phenotype in trans with another classic allele
- 21 patients
- Promoter variants in congenital adrenal hyperplasia (CAH) patients with only 1 known pathogenic variant
- 4
- Promoter variants in clinically unaffected individuals with no other CYP21A2 variant
- 6
- Conventional sequencing without promoter would not have suggested CAH or 21-OHD carrier status
- 10
Observational data: associations, not effects.
Original publication
Accurate diagnosis of congenital adrenal hyperplasia due to CYP21A2 variants requires promoter analysis. Eur J Endocrinol. Published 19 October 2025. doi:10.
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