Genetic characterization of a large cohort of Argentine 21-hydroxylase deficiency

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

CLINICAL ENDOCRINOLOGY

WILEY-BLACKWELL PUBLISHING, INC

Año: 2020

0300-0664

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 analyze the CYP21A2 gene defects in a large cohort of Argentine patients. Design: Molecular characterization of 628 patients (168 classical, 460 nonclassical, representing 1203 non-related 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 analyzed by structure-based in-silico studies.Results: The most frequent pathogenic variants were p.V282L (58%) in NC alleles and c.293-13 A/C>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 carriers frequency in our population.