Genetic characterization of a large cohort of Argentine 21‐hydroxylase Deficiency

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.

Congenital adrenal hyperplasia with homozygous and heterozygous mutations: a rare family case report

“…Mutational defects in the steroid 21-hydroxylase gene CYP21A2 causing steroid 21-hydroxylase deficiency account for over 90% of CAH cases [ 9 ]. Most genetic defects result from misalignments between the gene and the pseudogene during meiosis that result in deletions, large gene conversions, duplications, or the presence of more than one pathogenic variant in the same allele [ 10 ]. To date, more than 100 CYP21A2 mutations have been reported that are associated either with severe salt-wasting or simple virilizing phenotypes or with milder nonclassical phenotypes [ 11 ].…”