Genetic characterization of a large cohort of Argentine 21‐hydroxylase Deficiency. (3rd May 2020)

• Record Type: Journal Article
• Authors: Fernández, Cecilia S.; Taboas, Melisa; Bruque, Carlos D.; Benavides‐Mori, Belén; Belli, Susana; Stivel, Mirta; Oneto, Adriana; Pasqualini, Titania; Delea, Marisol; Espeche, Lucía D.; Kolomenski, Jorge E.; Alba, Liliana; Buzzalino, Noemí; Dain, Liliana
• Is Part Of: Clinical endocrinology. Volume 93:Number 1(2020)
• Page Start: 19
• Page End: 27
• Publication Date: 2020-05-03
• Subjects: 21‐Hydroxylase Deficiency -- Congenital Adrenal Hyperplasia -- CYP21A2 -- disease carriers frequency -- genetic variants -- genotype‐phenotype correlation -- RCCX module; Endocrinology -- Periodicals; 616.4005
• DOI: 10.1111/cen.14190
• Languages: English
• ISSNs: 0300-0664

Abstract

Abstract: Context: 21‐hydroxylase deficiency is the most common cause of Congenital Adrenal Hyperplasia. It presents as severe or classical forms—salt wasting and simple virilizing—and a mild or nonclassical (NC). Several studies have reported the frequency of pathogenic variants in different populations, although few of them included a large number of NC patients. Objective: To analyse the CYP21A2 gene defects in a large cohort of Argentine patients. Design: Molecular characterization of 628 patients (168 classical, 460 nonclassical, representing 1203 nonrelated alleles), 398 relatives, 126 partners. Methods: Genetic variants were assessed by allele‐specific PCR, PCR‐RFLP or direct sequencing. Deletions, duplications and large gene conversions (LGC) were studied by Southern blot/MLPA or long‐range PCR. Biological implications of novel variants were analysed by structure‐based in silico studies. Results: The most frequent pathogenic variants were p.V282L (58%) in NC alleles and c.293‐13C>G (31.8%) and p.I173N (21.1%) in classical. Deletions and LGC were found at low frequency (6.2%), 57 alleles had rare pathogenic variants, and 3 had novel variants: p.(S166F); p.(P189R), p.(R436L). Genotype‐phenotype correlation was observed in 98.6% of the cases, 11 asymptomatic first‐degree relatives had pathogenic variants in both alleles, and 21/126 partners were carriers. Conclusions: We conducted a comprehensive genetic characterization of the largest cohort of 21‐hydroxylase patients from the region. In particular, we add to the molecular characterization of a large number of NC patients and to the estimation of the disease carrier's frequency in our population.