应用全外显子组测序发现儿童罕见综合征耳聋

Whole⁃Exome Sequencing Reveals Pediatric Rare Syndromic Hearing Loss

目的探讨全外显子组测序方法对诊断儿童罕见综合征耳聋的意义。方法采用全外显子组测序技术对34例诊断为感音神经性听力损失患儿小家系进行分子病因学的检测和分析。结果19例患儿明确了分子病因,包括罕见的综合征耳聋4例,致病基因分别是HARS2、USH2A、GATA3和MITF;非综合征耳聋15例,包括GJB2基因突变8例,SLC26A4基因突变5例,MYO15A基因突变2例。HARS2基因的c.435_437del(p.K147del)和c.1403G>C(p.G468A)突变、USH2A基因的c.11389+1del突变、GATA3基因的c.1327delA(p.M443Wfs∗33)突变、MITF基因的c.627C>A(p.C209X)突变和MYO15A基因的c.8033_8057delinsG(p.N2678_D2686delinsS)突变均为首次报道。结论全外显子组测序技术有助于明确耳聋的致聋基因和突变,发现临床表型不明显的罕见综合征耳聋,并提示进一步完善相关系统或器官结构和功能的检查,对于临床诊断的准确性具有重要意义。

Objective To discuss the significance of genetic diagnosis of children with syndromic hearing loss by using whole⁃exome sequencing.Methods The clinical data of 34 children with sensorineural hearing loss were collected and the whole exons of genome of the children and their parents were sequenced and analyzed.Results Genetic causative gene and mutations have been identified in 19 children,including 4 genes(HARS2,USH2A,GATA3,MITF)related to rare syndromic hearing loss.Fifteen children were diagnosed with non⁃syndromichearing loss related gene,including 8 cases with GJB2 mutation,5 cases with SLC26A4 mutation and 2 cases with MYO15A mutation.Mutations of c.435_437del(p.K147del)and c.1403G>C(p.G468A)in gene HARS2,c.11389+1del in gene USH2A,c.1327delA(p.M443Wfs∗33)in gene GATA3,c.627C>A(p.C209X)in gene MITF and c.8033_8057delinsG(p.N2678_D2686delinsS)in gene MYO15A were first reported.Conclusions Whole⁃exome sequencing helps the accurate diagnosis of causes of hearing loss,especially for the rare syndromic hearing loss with atypical clinical manifestations.Information from genetic testing may highlight further recommended exams of structure and functions of related organs.