Centro Nacional de Genética Médica, Administración Nacional de Laboratorios e Institutos de Salud (ANLIS) 'Dr. Carlos G. Malbrán', Buenos Aires, Argentina.
Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
Clin Endocrinol (Oxf). 2020 Jul;93(1):19-27. doi: 10.1111/cen.14190. Epub 2020 May 3.
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.
To analyse the CYP21A2 gene defects in a large cohort of Argentine patients.
Molecular characterization of 628 patients (168 classical, 460 nonclassical, representing 1203 nonrelated alleles), 398 relatives, 126 partners.
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.
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.
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.
21-羟化酶缺乏症是先天性肾上腺皮质增生症最常见的病因。其表现为严重或经典型（失盐型和单纯男性化型）和轻度或非经典型（NC）。尽管有几项研究报告了不同人群中致病变异的频率，但其中很少有研究包含大量 NC 患者。
分析阿根廷大型患者队列中 CYP21A2 基因缺陷。
对 628 例患者（168 例经典型，460 例非经典型，代表 1203 个无关等位基因）、398 名亲属和 126 名伴侣进行分子特征分析。
通过等位基因特异性 PCR、PCR-RFLP 或直接测序评估遗传变异。通过 Southern blot/MLPA 或长距离 PCR 研究缺失、重复和大片段基因转换（LGC）。通过基于结构的计算机模拟研究分析新变异的生物学意义。
最常见的致病性变异是 NC 等位基因中的 p.V282L（58%）和经典型中的 c.293-13C>G（31.8%）和 p.I173N（21.1%）。低频率（6.2%）发现缺失和 LGC，57 个等位基因有罕见的致病性变异，3 个有新的变异：p.(S166F); p.(P189R), p.(R436L)。98.6%的病例存在基因型-表型相关性，11 名无症状一级亲属在两个等位基因中均携带致病性变异，21/126 名伴侣为携带者。
我们对该地区最大的 21-羟化酶患者队列进行了全面的遗传特征分析。特别是，我们增加了大量 NC 患者的分子特征分析，以及我们人群中疾病携带者频率的估计。
