Predicting phenotype in steroid 21-hydroxylase deficiency? Comprehensive genotyping in 155 unrelated, well defined patients from southern Germany
Predicting phenotype in steroid 21-hydroxylase deficiency? Comprehensive genotyping in 155 unrelated, well defined patients from southern Germany
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DOI：
10.1210/jc.85.3.1059
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发表时间：
2000-03-01
影响因子：
5.8
通讯作者：
Schwarz, HP
中科院分区：
文献类型：
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作者：
Krone, N;Braun, A;Schwarz, HP
先天性肾上腺增生症（CAH）是一组常染色体隐性遗传疾病。 CAH 最常由类固醇 21-羟化酶缺乏引起。在 155 名明确的无关 CAH 患者中对 CYP21 失活突变的频率和基因型-表型关系进行了表征。我们能够阐明 310 个致病等位基因中的 306 个（诊断敏感性，98.7%）。最常见的突变是内含子2剪接位点突变（30.3%），其次是基因缺失（20.3%）、I172N突变（19.7%）和大基因转换（7.1%）。检测到五个点突变，这些突变在其他 CAH 队列中尚未描述。根据其预测的功能后果并与临床表型进行比较，将基因型分为 4 个突变组（无效、A、B 和 C）。无效突变 (ppv(null)) 的阳性预测值为 100%，因为所有携带这些突变的患者均具有耗盐表型。在突变组 A（内含子 2 剪接位点突变为纯合或杂合形式且无效突变）中，出现盐消耗性 CAH 的 ppv(A) 为 90%。在预测导致单纯性男性化 CAH（I172N 纯合子或具有更严重突变的复合杂合子形式）的 B 组中，ppv(B) 为 74%。在 C 组（P30L、V281L、P453S 纯合或具有更严重突变的复合杂合形式）中，ppv(C) 为 64.7%，表现出非经典形式的 CAH，但排除 P30L 突变时为 90%。因此，一般来说，具有最严重或最轻微突变的患者表现出良好的基因型-表型关系。在中等严重程度的突变组中观察到相当程度的差异。迄今为止，改变α-羟化酶基因表达和类固醇激素作用的不确定因素可能解释了这些表型表达的差异。
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders. CAH is most often caused by deficiency of steroid 21-hydroxylase. The frequency of CYP21-inactivating mutations and the genotype-phenotype relationship were characterized in 155 well defined unrelated CAH patients. We were able to elucidate 306 of 310 disease-causing alleles (diagnostic sensitivity, 98.7%). The most frequent mutation was the intron 2 splice site mutation (30.3%), followed by gene deletions (20.3%), the I172N mutation (19.7%) and large gene conversions (7.1%). Five point mutations were detected that have not been described in other CAH cohorts. Genotypes were categorized in 4 mutation groups (null, A, B, and C) according to their predicted functional consequences and compared to the clinical phenotype. The positive predictive value for null mutations (ppv(null)) was 100%, as all patients with these mutations had a salt wasting phenotype. In mutation group A (intron 2 splice site mutation in homozygous or heterozygous form with a null mutation), the ppv(A) to manifest with salt-wasting CAH was 90%. In group B predicted to result in simple virilizing CAH (I172Nin homozygous or compound heterozygous form with a more severe mutation), ppv(B) was 74%. In group C (P30L, V281L, P453S in homozygous or compound heterozygous form with a more severe mutation), ppv(C) was 64.7% to exhibit the nonclassical form of CAH, but 90% when excluding the P30L mutation. Thus, in general, a good genotype-phenotype relationship is shown in patients with either the severest or the mildest mutations. A considerable degree of divergence is observed within mutation groups of intermediate severity. As yet undefined factors modifying al-hydroxylase gene expression and steroid hormone action are likely to account for these differences in phenotypic expression.