25个先天性肾上腺皮质增生症家系的遗传学分析及产前诊断

Genetic analysis and prenatal diagnosis for 25 Chinese pedigrees affected with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

目的对先天性肾上腺皮质增生症家系进行CYP21A2基因突变分析,探讨其遗传学病因,并为其家系产前诊断提供依据。方法应用位点特异性PCR-酶切多态分析、多重连接依赖探针扩增技术和CYP21A2基因全长测序技术,对25个先天性肾上腺皮质增生症家系进行CYP21A2基因突变分析。对患病高风险胎儿进行产前基因检测,明确胎儿基因型。结果在25对夫妇的50个致病等位基因中,有16个等位基因发生大片段缺失或转换突变;占总等位基因的32%,包括9个CYP21A2基因缺失突变、6个CYP21A1P/CYP21A2嵌合基因和1个部分转换突变;有34个为微小突变,占总等位基因的68%,其中9种突变均为假基因来源的微转换突变,4种为自发突变。在4种自发突变中,CYP21A2基因c.62G>A(p.Trp21X).突变为新发现突变。在28例高风险胎儿产前基因检测结果显示8例胎儿受累。结论对先天性肾上腺皮质增生症患者和携带者的基因突变检测明确了25个家系的遗传学病因,为家系的遗传咨询和产前诊断提供了依据。

Objective To identify pathogenic mutations in 25 Chinese pedigrees affected with congenital adrenal hyperplasia (CAH).Methods Mutations of the CYP21A2 gene were detected with locus-specific PCR/restriction endonuclease analysis,multiplex ligation-dependent probe amplification assay, and direct sequencing of the entire CYP21A2 gene.Prenatal diagnosis was offered to fetuses at risk for CAH.Results All 50 alleles of the CYP21A2 gene,carried by the 25 pedigrees were successfully delineated. Large deletions and conversions have accounted for 16(32%)of the alleles,which included 9entire CYP21A2 gene deletions,6 chimeric CYP21A1P/CYP.21A2 genes,and 1partial conversion of the CYP21A2 gene.For the remaining 34 alleles,there were 9micro-conversions and 4 de novo mutations [including a previously unreported c.62G>A (p.Trp21X)mutation].Prenatal diagnosis was provided for 28 fetuses with a high risk for CAH,among whom 8were found to be affected.Conclusion The detection of CYP21A2 gene mutations can facilitate appropriate genetic counseling and prenatal diagnosis for the affected pedigrees.