Clinical Phenotype and Mutation Spectrum of the CYP21A2 Gene in Patients with Steroid 21-Hydroxylase Deficiency

Abstract

Steroid 21-hydroxylase deficiency is caused by inactivating mutations in the CYP21A2 gene. This paper reports on the mutation spectrum and the genotype-phenotype correlation of 21-hydroxylase deficiency. 72 unrelated patients with congenital adrenal hyperplasia (CAH) were included. Molecular analysis of CYP21A2 was performed, via the multiplex ligation-dependent probe amplification (MLPA) analysis and sequence-specific differenzial PCR amplification of the CYP21A2 and CYP21A1P genes, using 4 pair-wise sequence-specific primers, followed by sequencing of the entire CYP21A2 gene. Large gene deletions were identified in 45 (31.3%) of the 144 unrelated CAH alleles, whereas the most frequent point mutations were intron 2 splice mutations (c.293-13A>G) (41/144, 28.5%). The MLPA analysis successfully identified 23 of 72 patients (31.9%) with single copy deletion in CYP21A2. This paper describes a rapid and accurate method for the molecular diagnosis of 21-hydroxylase deficiency, which relies on the identification of point mutations and structural rearrangements within the CYP21A2 gene.

Hormonal disturbances due to severe and mild forms of congenital adrenal hyperplasia are already detectable in neonatal life

“…The patients were grouped by genotype according to disease severity, and in general, a good correlation between genotype and phenotype later in life has been reported in other studies . To our knowledge, the present study is the first to compare CAH genotypes with neonatal hormonal profiles.…”

Prenatal diagnosis of steroid 21-hydroxylase-deficient congenital adrenal hyperplasia

“…About 40 per cent of the foetuses carried deletions either on one or both the chromosomes. High frequency of deletions has also been reported in other populations2122 but not in Indian patients232425. The reason for detection of high frequency of deletions could be MLPA, a highly sensitive method used in this study.…”

<b><i>CYP21A2</i></b> Gene Pathogenic Variants: A Multicenter Study on Genotype–Phenotype Correlation from a Portuguese Pediatric Cohort

“…Usually, the correlation is higher than 80–90% for the pathogenic variants associated with low enzymatic activity and a SW phenotype (groups 0 and A) and for the pathogenic variants of the group C (NC phenotype), but lower for the group B pathogenic variant (usually associated with a SV phenotype) [6, 9, 11-13, 24, 39, 44-46]. In our population, the correlation was also lower for group B associated pathogenic variant (80% compared to exceeding 90% concordance on groups 0, A, and C), but with no statistical significance observed.…”