四例先天性高胰岛素血症患儿的基因变异分析

Analysis of genetic variants in four children with congenital hyperinsulinemia

目的对4例先天性高胰岛素血症患儿的家系进行基因变异分析,探讨其可能的致病原因。方法对4例患儿进行全外显子测序,并对变异位点进行Sanger测序验证。结果全外显子的测序检出ABCC8基因变异4个,GLUD1基因变异1个。例1 ABCC8基因存在c.382G>A杂合变异;例2 ABCC8基因存在c.698T>C和c.4213G>A复合杂合变异,同时合并15号染色体短臂14.9 Mb重复;例3 ABCC8基因存在c.331G>A杂合变异;例4 GLUD1基因存在c.955T>C杂合变异。其中ABCC8基因c.698T>C及GLUD1基因c.955T>C变异未见报道。根据美国医学遗传学与基因组学学会遗传变异分类标准与指南,ABCC8基因c.382G>A(p.Glu128Lys)、c.698T>C(p.Met233Thr)、c.4213G>A(p.Asp1405Asn)变异和GLUD1基因c.955T>C(p.Tyr319His)变异判定为可能致病性变异(PM1+PM2+PP3+PP4;PM1+PM2+PM5+PP3+PP4;PM1+PM2+PP3+PP4和PS1+PM1+PM2+PP3),ABCC8基因c.331G>A(p.Gly111Arg)变异判定为临床意义不明(PM1+PM2+PP4)。结论ABCC8基因和GLUD1基因变异可能为4例患者的致病原因,基因检测结果可为临床诊断和遗传咨询提供依据。

Objective To explore the genetic basis of four children with congenital hyperinsulinemia(CHI).Methods The four children were subjected to high-throughput whole exome sequencing(WES).Candidate variants were validated by Sanger sequencing.Results WES analysis has identified 4 variants in the ABCC8 gene and 1 variant in GLUD1,including a ABCC8 c.382G>A variant in case 1,compound heterozygous c.698T>C and c.4213G>A variants of the ABCC8 gene concomitant with a de novo 14.9 Mb microduplication of chromosome 15 in case 2,and ABCC8 c.331G>A variant in case 3,and de novo c.955T>C variant of the GLUD1 gene in case 4.Of these,c.698T>C of the ABCC8 gene and c.955T>C of the GLUD1 gene were unreported previously.Based on the American College of Medical Genetics and Genomics guidelines,the c.382G>A(p.Glu128Lys),c.698T>C(p.Met233Thr)and c.4213G>A(p.Asp1405Asn)variants of ABCC8 gene and c.955T>C(p.Tyr319His)variant of GLUD1 gene were predicted to be likely pathogenic(PM1+PM2+PP3+PP4,PM1+PM2+PM5+PP3+PP4,PM1+PM2+PP3+PP4 and PS1+PM1+PM2+PP3),and the c.331G>A(p.Gly111Arg)variant of ABCC8 gene was predicted to be uncertain significance(PM1+PM2+PP4).Conclusion The variants of the ABCC8 and GLUD1 genes probably underlay the pathogenesis of CHI in the four patients.Above results have facilitated clinical diagnosis and genetic counseling for the affected families.