Comprehensive Genetic Analysis of 182 Unrelated Families with Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency
Comprehensive Genetic Analysis of 182 Unrelated Families with Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency
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DOI：
10.1210/jc.2010-0319
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发表时间：
2011-01-01
影响因子：
5.8
通讯作者：
Merke, Deborah P.
中科院分区：
文献类型：
--
作者：
Finkielstain, Gabriela P.;Chen, Wuyan;Merke, Deborah P.
背景资料：遗传分析是常见的先天性肾上腺皮质增生症（CAH）患者由于21-羟化酶deficiency.Study Objective：本研究的目的是描述全面的CYP 21 A2突变分析在一个大的队列CAH patients.Methods：有针对性的CYP 21 A2突变分析进行了213例患者和232名父母从182个无关的家庭。在靶向突变分析未发现阳性突变的患者中，对CYP 21 A2的完整外显子进行测序。拷贝数变异和缺失使用Southern印迹分析和PCR方法确定。基因型与表型相关。结果：在我们的异质性美国队列中，有针对性的CYP 21 A2突变分析没有发现突变的一个等位基因在19个先证者（10.4%）。测序鉴定了6个新突变（p.Gln262fs、IVS 8 +1G > A、IVS 9 -1G > A、p.R408H、p.Gly424fs、p.R426P）和9个先前报道的罕见突变。大多数患者（79%）为复合杂合子，69%的非经典（NC）患者为经典和NC突变的复合杂合子。2.7%的先证者和1.9%和0.9%的来自信息家族的患者分别存在重复的CYP 21 A2单倍型、从头突变和单亲二体。基因型准确预测表型在90.5，85.1，和97.8%的患者与盐浪费，简单男性化，和NC突变，respectively.Conclusions：广泛的遗传分析超出有针对性的CYP 21 A2突变检测往往需要准确地确定基因型CAH患者由于复杂的遗传变异的高频率。（临床内分泌代谢杂志96：E161-E172，2011）
Background: Genetic analysis is commonly performed in patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency.Study Objective: The objective of the study was to describe comprehensive CYP21A2 mutation analysis in a large cohort of CAH patients.Methods: Targeted CYP21A2 mutation analysis was performed in 213 patients and 232 parents from 182 unrelated families. Complete exons of CYP21A2 were sequenced in patients in whom positive mutations were not identified by targeted mutation analysis. Copy number variation and deletions were determined using Southern blot analysis and PCR methods. Genotype was correlated with phenotype.Results: In our heterogeneous U.S. cohort, targeted CYP21A2 mutation analysis did not identify mutations on one allele in 19 probands (10.4%). Sequencing identified six novel mutations (p.Gln262fs, IVS8+1G > A, IVS9-1G > A, p.R408H, p.Gly424fs, p.R426P) and nine previously reported rare mutations. The majority of patients (79%) were compound heterozygotes and 69% of nonclassic (NC) patients were compound heterozygous for a classic and a NC mutation. Duplicated CYP21A2 haplotypes, de novo mutations and uniparental disomy were present in 2.7% of probands and 1.9 and 0.9% of patients from informative families, respectively. Genotype accurately predicted phenotype in 90.5, 85.1, and 97.8% of patients with salt-wasting, simple virilizing, and NC mutations, respectively.Conclusions: Extensive genetic analysis beyond targeted CYP21A2 mutational detection is often required to accurately determine genotype in patients with CAH due to the high frequency of complex genetic variation. (J Clin Endocrinol Metab 96: E161-E172, 2011)