Spectrum of CYP21A2 Variants: A Retrospective Single-center Study from a Tertiary Healthcare Center in Türkiye

CYP21A2 Variants in a Turkish Cohort

Abstract

Objective: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is a common autosomal recessive disorder caused by pathogenic variants in the CYP21A2 gene. The spectrum of variants differs significantly among populations because of complex genetic recombination events involving the neighbouring CYP21A1P pseudogene. This study aimed to evaluate the variant distribution, genotype frequencies, and clinical indications in a large Turkish cohort referred for CYP21A2 genetic analysis.
Methods: A total of 252 pediatric patients who underwent CYP21A2 gene sequencing and multiplex ligation-dependent probe amplification at a single tertiary center were retrospectively analyzed. Genotype and allele frequencies of classical point variants, small indels, large deletions, and pseudogene-derived micro-conversions were calculated and correlated with clinical referral indications.
Results: Among the 252 patients, 133 (52.8%) were, by both sequencing and copy number analyses, found to carry no reportable variants. The most frequent pathogenic variant identified was c.844G>T p.(Val282Leu), found in the homozygous state in 20 patients (7.9%) and in 77 alleles in total. Other prevalent, severe variants included the intron 2 splice- site variant c.293-13A/C>G and the pseudogene-derived p.(Gln319*) variant. Structural rearrangements, including exon-specific micro-conversions (most notably involving exon 4), large multi-exon deletions, and complex allele combinations such as CAH-X, were detected in 21 patients (8.3%). Hirsutism, abnormal menstruation, and precocious puberty were the leading indications for genetic testing in adolescent cohorts, whereas scrotal/genital hyperpigmentation and abnormal neonatal screening predominated in infancy.
Conclusion: The genetic architecture of CYP21A2 in Türkiye is characterized by a high prevalence of the non-classic c.844G>T p.(Val282Leu) variant alongside a diverse spectrum of severe pseudogene-mediated conversions and deletions. These findings underscore the clinical necessity of using parallel sequencing and copy number detection strategies to achieve accurate molecular diagnosis and genetic counselling in the Turkish population.