Ⅳ型Waardenburg综合征致病基因突变分析

Mutation Analysis of Type Ⅳ Waardenburg Syndrome

目的报告1例Ⅳ型Waardenburg综合征(Waardenburg syndrome type 4,WS4)患儿并探讨其基因突变特点。方法采集先证者及其父母的临床资料和外周血,提取基因组DNA,应用全外显子组高通量测序技术筛查先证者致病基因,对先证者及其父母进行变异位点的Sanger测序验证。结果先证者SOX10基因4号外显子发生c.777del杂合突变(NM_006941.4),导致SOX10蛋白从第259位氨基酸开始发生移码(第259位氨基酸由天冬氨酸转变为谷氨酸),到其后第27位氨基酸位置时终止[c.777del(p.D259Efs*27)]。先证者父母SOX10基因序列测序分析该位点无变异,因此患儿该位点为自发突变。根据美国医学遗传学与基因组学学会(ACMG)指南和ClinGen序列变异解释专家组对指南标准的应用建议,该变异为可能致病性(PVS1_Strong+PP4+PM2_Supporting)。结论SOX10基因移码突变c.777del(p.D259Efs*27)为新发现的突变,该杂合突变是此例患儿WS4的致病原因。

Objective To report a child with Waardenburg syndrome typeⅣ(WS4)and to investigate the gene mutations characteristics of the child.Methods Clinical data and peripheral blood DNA of the proband and his parents were collected.High-throughput whole-exome gene sequencing was used to analyze the mutation and Sanger sequencing verification was performed.Results The proband harbored a c.777del heterozygous mutation(NM_006941.4)in exon 4 of the SOX10 gene.This mutation resulted in a frameshift,causing a translation from amino acid position 259,where aspartic acid was replaced by glutamic acid,leading to a premature stop codon[c.777del(p.D259Efs*27)].It was a de novo mutation.According to the American College of Medical Genetics and Genomics(ACMG)guidelines and the ClinGen Sequence Variant Interpretation Working Group recommendations for using ACMG criteria,this may be a pathogenic variant(PVS1_Strong+PP4+PM2_Supporting).Conclusion The novel frameshift mutation c.777del(p.D259Efs*27)in the SOX10 gene was a de novo mutation,which leads to WS4 in this child.