DFNB3型耳聋患儿MYO15A基因变异分析

Analysis of MYO15A variation in children with DFNB3

目的探讨常染色体隐性非综合征耳聋3型致病基因MYO15A基因的变异特点及临床特征。方法回顾性分析自2016年11月至2019年2月在郑州大学第一附属医院遗传与产前诊断中心进行耳聋基因高通量测序的108个非综合征型耳聋家庭的听力及测序数据,总结MYO15A基因的变异情况。结果共有来自8个家庭的9例耳聋患儿检测到MYO15A基因复合杂合变异,占所有耳聋家庭的7.4%(8/108),变异位点分别为c.5910+1G>A/c.9417_9418insTA、c.4234T>G/c.8324G>T、c.3926A>T/c.5002delC、c.9690+1G>A/c.10257_10259delCTT、c.8324G>T/c.10419_10423delCAGCT、c.4519C>T/c.6454G>C、c.6177+1G>T/c.10257_10259delCTT、c.5692C>T/c.7396-1G>A,所有患儿均为重度至极重度耳聋表型。14个变异位点中,12个变异位于蛋白的重要结构域中,包括motor结构域5个,FERM结构域3个、MyTH4结构域3个,IQ基序1个,其中c.3926A>T、c.4234T>G、c.4519C>T、c.5002delC、c.6454G>C、c.8324G>T、c.9417_9418insTA、c.10419_10423delCAGCT这8个变异经人类基因组突变数据库专业版(截至2020年2月)查询尚无文献报道,根据美国医学遗传学与基因组学学会制定的变异分类标准与指南,6个已有文献报道的变异以及本研究新发现的c.4519C>T、c.5002delC、c.9417_9418insTA、c.10419_10423delCAGCT评定为致病变异,c.8324G>T评定为可能致病变异,c.3926A>T、c.4234T>G、c.6454G>C评定为临床意义不明变异。结论MYO15A基因在中国耳聋人群主要以复合杂合变异形式致病,临床表型多为重度至极重度耳聋,变异位点主要集中于motor、FERM、MyTH4结构域中。

Objective To analyze the genetic and clinical characteristics of MYO15A variants associated non-syndromic autosomal recessive deafness3(DFNB3).Methods The hearing test and high-throughput sequencing data of 108 families with non-syndromic hearing loss,who visited the Center of Genetics and Prenatal Diagnosis in the First Affiliated Hospital of Zhengzhou University from November 2016 to February 2019,were retrospectively analyzed to investigate the characteristics of MYO15A variation.Results Compound heterozygous MYO15A variations were detected in nine patients from eight families,accounting for 7.4%of all 108 families.The variants were c.5910+1G>A/c.9417_9418insTA,c.4234T>G/c.8324G>T,c.3926A>T/c.5002delC,c.9690+1G>A/c.10257_10259delCTT,c.8324G>T/c.10419_10423delCAGCT,c.4519C>T/c.6454G>C,c.6177+1G>T/c.10257_10259delCTT and c.5692C>T/c.7396-1G>A.All patients had severe to profound hearing loss.Among the 14 variations,12 variations were located in the main structural domains,including 5 in motor domain,3 in FERM domain,3 in MyTH4 domain and 1 in IQ motif.The c.3926A>T,c.4234T>G,c.4519C>T,c.5002delC,c.6454G>C,c.8324G>T,c.9417_9418insTA and c.10419_10423delCAGCT had not been reported in the Human Gene Mutation Database up to February 2020.According to the guidelines of the American College of Medical Genetics and Genomics(ACMG),6 reported variants and the first reported c.4519C>T,c.5002delC,c.9417_9418insTA and c.10419_10423delCAGCT were identified as pathogenic variants,while c.8324G>T was likely pathogenic variant,and c.3926A>T,c.4234T>G and c.6454G>C were variants of uncertain significance.Conclusions The variations of MYO15A in patients with DFNB3 are mainly complex heterozygous.The clinical phenotypes are mostly severe to profound hearing loss,and the mutation loci are mainly in the motor,FERM and MyTH4 domains.