Endocrinology Service, Hospital de Pediatria Garrahan, Buenos Aires, Argentina.
Clin Endocrinol (Oxf). 2011 Oct;75(4):427-35. doi: 10.1111/j.1365-2265.2011.04123.x.
To report genotype-phenotype correlation in a large cohort of patients.
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).
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.
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 [PromCYP21A1P; 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.
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.
报告大样本患者的基因型-表型相关性。
对来自阿根廷的经典型和非经典型（NC）21-羟化酶缺乏症的 866 例无关染色体的 CYP21A2 基因进行研究。
通过等位基因特异性聚合酶链反应、限制性片段长度多态性（RFLP）或Southern 印迹分析分析 11 种最常见的突变。当一个等位基因未检测到突变或基因型-表型相关性缺乏时，进行基因测序。
11 种常见突变筛查可检测到 88.1%的受影响等位基因（NC 为 80.3%，经典型为 95.2%）。p.V281L、IVS2-13A/C>G（In2）和基因缺失及大片段基因转换是最常见的突变。在失盐型（SW）中，p.V281L 最常见（35.2%），在单纯男性化中 p.I172N 最常见（37.3%），在 NC CAH 中 p.V281L 最常见（54.1%）。在 15 个 p.P30L 突变等位基因中，有 7 个检测到 CYP21A1P/CYP21A2 基因嵌合体[PromCYP21A1P;p.P30L]，6 个为单核苷酸取代，2 个与突变连锁，p.[P30L;V281L]和[p.P30L;IVS2-13A/C>G;p.Q318X]。在 2 例 SW 患者中，发现了一种新的无义突变 p.Q41X。在 3 例 p.V281L 突变患者中，表型比基因型预测的更严重。序列分析显示携带 p.V281L 突变的等位基因存在内含子改变[IVS2+5G>A;p.V281L]。这种 p.V281L 突变等位基因的异常剪接解释了临床表型。
通过 11 种突变筛查研究可检测到 CYP21A2 受影响等位基因的高比例。基因型-表型相关性较高，但当表型比基因型预测的更严重时，应排除一个等位基因中存在两种改变的情况。
