期刊
MARROW
卷 1364, 期 -, 页码 5-10出版社
BLACKWELL SCIENCE PUBL
DOI: 10.1111/nyas.12864
关键词
CYP21A2; genotype; phenotype; p.R366H; congenital adrenal hyperplasia
资金
- Intramural NIH HHS [Z01 HD000072] Funding Source: Medline
- NIAMS NIH HHS [R01 AR067066, R01 AR065932, AR06592, AR06066] Funding Source: Medline
- NIA NIH HHS [R01 AG023176, AG23176, AG40132, R01 AG040132] Funding Source: Medline
- NICHD NIH HHS [R37 HD000072, HD00072] Funding Source: Medline
- NIDDK NIH HHS [R01 DK080459, DK80459] Funding Source: Medline
Congenital adrenal hyperplasia (CAH) owing to 21-hydroxylase deficiency is caused by the autosomal recessive inheritance ofmutations 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 raremutation 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.
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