Khattab Ahmed, Yuen Tony, Al-Malki Sultan, Yau Mabel, Kazmi Diya, Sun Li, Harbison Madeleine, Haider Shozeb, Zaidi Mone, New Maria I
Division of Adrenal Steroid Disorders, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York.
Department of Medicine, The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, New York.
Ann N Y Acad Sci. 2016 Jan;1364(1):5-10. doi: 10.1111/nyas.12864. Epub 2015 Aug 20.
Congenital adrenal hyperplasia (CAH) owing to 21-hydroxylase deficiency is caused by the autosomal recessive inheritance of mutations in the gene CYP21A2. CYP21A2 mutations lead to variable impairment of the 21-hydroxylase enzyme, which, in turn, is associated with three clinical phenotypes, namely, salt wasting, simple virilizing, and nonclassical CAH. However, it is known that a given mutation can associate with different clinical phenotypes, resulting in a high rate of genotype-phenotype nonconcordance. We aimed to study the genotype-phenotype nonconcordance in a family with three siblings affected with nonclassical CAH. All had hormonal evidence of nonclassical CAH, but this phenotype could not be explained by the genotype obtained from commercial CYP21A2 genetic testing, which revealed heterozygosity for the maternal 30 kb deletion mutation. We performed Sanger sequencing of the entire CYP21A2 gene in this family to search for a rare mutation that was not covered by commercial testing and found in the three siblings a second, rare c.1097G>A (p.R366H) mutation in exon 8. Computational modeling confirmed that this was a mild mutation consistent with nonclassical CAH. We recommend that sequencing of entire genes for rare mutations should be carried out when genotype-phenotype nonconcordance is observed in patients with autosomal recessive monogenic disorders, including CAH.
由于21-羟化酶缺乏导致的先天性肾上腺增生(CAH)是由CYP21A2基因突变的常染色体隐性遗传引起的。CYP21A2基因突变导致21-羟化酶的不同程度损伤,进而与三种临床表型相关,即失盐型、单纯男性化型和非经典型CAH。然而,已知特定突变可与不同临床表型相关,导致基因型-表型不一致的发生率很高。我们旨在研究一个有三名患非经典型CAH的兄弟姐妹的家庭中的基因型-表型不一致情况。所有人都有非经典型CAH的激素证据,但这种表型无法用商业CYP21A2基因检测获得的基因型来解释,该检测显示母亲30 kb缺失突变的杂合性。我们对这个家庭的整个CYP21A2基因进行了桑格测序,以寻找商业检测未涵盖的罕见突变,并在这三名兄弟姐妹中发现了外显子8中的第二个罕见的c.1097G>A(p.R366H)突变。计算模型证实这是一个与非经典型CAH一致的轻度突变。我们建议,当在包括CAH在内的常染色体隐性单基因疾病患者中观察到基因型-表型不一致时,应进行整个基因的罕见突变测序。