Targeted gene panel sequencing for molecular diagnosis of congenital adrenal hyperplasia

先天性肾上腺增生 CYP17A1型 遗传学 生物 候选基因 多重连接依赖探针扩增 基因分型 基因型 错义突变 基因 甾体11β-羟化酶 表型 外显子 内分泌学 类固醇 激素
作者
Wencui Wang,Rulai Han,Zuwei Yang,Sichang Zheng,Haorong Li,Zhihan Wan,Yan Qi,Shouyue Sun,Lei Ye,Guang Ning
出处
期刊:The Journal of Steroid Biochemistry and Molecular Biology [Elsevier BV]
卷期号:211: 105899-105899 被引量:19
标识
DOI:10.1016/j.jsbmb.2021.105899
摘要

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive genetic diseases caused by genetic deficiency in nine genes encoding steroidogenesis enzymes and cofactors. To establish a targeted next-generation sequencing (NGS) assay for all nine CAH candidate genes. We developed a customized targeted NGS assay of CAH candidate genes (CYP21A2, CYP17A1, CYP11B1, StAR, CYP11A1, POR, HSD3B2, H6PD, CYP11B2) and apply this assay plus MLPA of CYP21A2 in a total of 469 patients with CAH like signs and symptoms. We totally identified 125 variants with seven variant types in eight genes. Variant types included missense variant (46.8 %), splicing variant (21.5 %), small indel (12.5 %), large structure variation (11.8 %), nonsense variant (4.1 %), UTR variant (2.9 %), synonymous variant (0.3 %). Successful genotyping, defined as biallelic pathogenic or likely pathogenic variants, was achieved in 98.5 % (336/341) of cases, including biallelic variants in CYP21A2 (n = 254), CYP17A1 (n = 45), CYP11B1 (n = 23), StAR (n = 7), HSD3B2 (n = 4), POR (n = 1), CYP11A1 (n = 1) and CYP11B2 (n = 1) gene. Importantly, the assay found one patient with CYP11B1 deficiency, one patient with non-classic POR deficiency and two patients with non-classic CYP17A1 deficiency while clinically diagnosed differently. Our NGS-based assay plus MLPA of CYP21A2 is a useful tool to genotype all subtypes of CAH. The test successfully achieved genotype in 98.5 % of patients with clinically determined CAH. It also efficiently facilitated the diagnosis of CAH in patients with rare subtypes as well as non-classic phenotypes.
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