Steroid 21‐hydroxylase gene mutational spectrum in 454 Argentinean patients: genotype–phenotype correlation in a large cohort of patients with congenital adrenal hyperplasia
- 7 September 2011
- journal article
- research article
- Published by Wiley in Clinical Endocrinology
- Vol. 75 (4), 427-435
- https://doi.org/10.1111/j.1365-2265.2011.04123.x
Abstract
Objective To report genotype-phenotype correlation in a large cohort of patients. Context Study of the CYP21A2 gene in 866 unrelated chromosomes of 21-hydroxylase deficiency in Argentinean patients with classic and nonclassic (NC) forms of congenital adrenal hyperplasia (CAH). Methods Eleven most common mutations were analysed by allele-specific polymerase chain reaction, restriction fragment length polymorphism (RFLP) or southern blot analysis. Gene sequencing was performed when no mutation was detected in one allele or the genotype-phenotype correlation was lacking. Results The 11-most-common-mutation screening allowed for the detection of 88.1% of affected alleles (80.3% in the NC and 95.2% in the classic forms). p.V281L, IVS2-13A/C>G (In2) and gene deletions and large gene conversions were the most prevalent mutations. In2 (35.2%) in salt wasting (SW), p.I172N (37.3%) in simple virilizing and p.V281L (54.1%) in NC CAH were the most prevalent mutations within the clinical forms. In 7/15 p.P30L mutation alleles, a chimeric CYP21A1P/CYP21A2 gene [Prom-CYP21A1P; p.P30L] was detected, while 6/15 represented a single-nucleotide substitution, and in 2/15 linkage with mutations, p.[P30L; V281L] and [p. P30L; IVS2-13A/C > G; p.Q318X] was found. In two SW patients, a novel nonsense mutation, p.Q41X, was observed. In three p.V281L mutation patients, the phenotype was more severe than predicted by genotype. Sequence analysis revealed an intronic alteration in the allele carrying the p.V281L mutation [IVS2 + 5G > A; p.V281L]. An aberrant splicing in this p.V281L mutated allele explains the clinical phenotype. Conclusions A high percentage of CYP21A2 affected alleles is detected by the 11-mutation screening study. Genotype-phenotype correlation was high, but when the phenotype is more severe than predicted by genotype, presence of two alterations in one allele should be ruled out.This publication has 31 references indexed in Scilit:
- Comprehensive Genetic Analysis of 182 Unrelated Families with Congenital Adrenal Hyperplasia due to 21-Hydroxylase DeficiencyJournal of Clinical Endocrinology & Metabolism, 2011
- Nonclassic Congenital Adrenal HyperplasiaInternational Journal of Pediatric Endocrinology, 2010
- High variability in CYP21A2 mutated alleles in Spanish 21‐hydroxylase deficiency patients, six novel mutations and a founder effectClinical Endocrinology, 2006
- Substitutions in the CYP21A2 promoter explain the simple-virilizing form of 21-hydroxylase deficiency in patients harbouring a P30L mutationClinical Endocrinology, 2005
- Genetic Analysis of Japanese Patients with 21-Hydroxylase Deficiency: Identification of a Patient with a New Mutation of a Homozygous Deletion of Adenine at Codon 246 and Patients without Demonstrable Mutations within the Structural Gene for CYP21Journal of Clinical Endocrinology & Metabolism, 2002
- Congenital Adrenal Hyperplasia due to 21-Hydroxylase DeficiencyEndocrine Reviews, 2000
- Molecular Genotyping in Brazilian Patients with the Classical and Nonclassical Forms of 21-Hydroxylase DeficiencyJournal of Clinical Endocrinology & Metabolism, 1998
- Population-Wide Evaluation of Disease Manifestation in Relation to Molecular Genotype in Steroid 21-Hydroxylase (CYP21) Deficiency: Good Correlation in a Well Defined PopulationJournal of Clinical Endocrinology & Metabolism, 1997
- Mutations of the Steroid 21-Hydroxylase Gene in an Argentinian Population of 36 Patients with Classical Congenital Adrenal HyperplasiaJournal of Pediatric Endocrinology and Metabolism, 1997
- Disease expression and molecular genotype in congenital adrenal hyperplasia due to 21-hydroxylase deficiency.JCI Insight, 1992