3型进行性家族性肝内胆汁淤积症病例临床及遗传学分析

Clinical and genetic analysis of cases of progressive familial intrahepatic cholestasis type 3

目的对2例胆汁淤积性肝病患者进行临床及遗传学分析,明确胆汁淤积的具体病因。方法采集2例患者的临床资料及家系成员的病史,应用全外显子测序技术对患者进行基因变异检测,并对疑似致病性变异的患者及其父母进行Sanger测序验证及生物信息学分析。结果全外显子测序显示,患者1(男,16岁)的ABCB4基因存在源自父亲的c.646C>T和源自母亲的c.927T>A的复合杂合突变;患者2(女,17岁)的ABCB4基因存在源自父亲的c.2784-1G>A和源自母亲的c.646C>T的复合杂合突变。c.646C>T、c.927T>A、c.2784-1G>A均为既往未见报道的新变异位点。结论本研究的2例患者均为ABCB4基因突变引起的3型进行性家族性肝内胆汁淤积症,本研究也丰富了ABCB4的致病变异谱;全外显子组测序技术为病因分析提供了可靠的诊断工具。

Objective To conduct clinical and genetic analysis in two cases of cholestatic liver disease to determine the specific etiology of cholestasis.Methods Clinical data and the medical histories in family members of two cases were collected.The gene variation was detected by whole-exome sequencing technology.Sanger sequencing validation and bioinformatics analysis were performed on patients and their parents with suspected pathogenic mutations.Results Whole-exome sequencing showed that the ABCB4 gene of case 1(a male,16 years old)had compound heterozygous mutations of c.646C>T from the father and c.927T>A from the mother,while the ABCB4 gene of case 2(a female,17 years old)had a compound heterozygous mutation of c.2784-1G>A from the father and c.646C>T from the mother.New mutation sites that had not been previously reported were c.646C>T,c.927T>A,and c.2784-1G>A.Conclusion In this study,both cases had progressive familial intrahepatic cholestasis type 3(PFIC-3)caused by ABCB4 gene mutations,and it also enriched the ABCB4 pathogenic variant spectrum.Whole-exome sequencing technology provides a reliable diagnostic tool for etiological analysis.