一个POU4F3基因变异所致常染色体显性聋15型家系的遗传学分析

Genetic Analysis of a Pedigree with Autosomal Dominant Deafness Type 15 Caused by POU4F3 Gene Variation

目的对一个常染色体显性非综合征型进行性听力减退的患者家系进行基因分析,以明确其可能的遗传学病因。方法应用全外显子组测序方法对先证者进行基因分析,应用Sanger测序法对可疑致病位点进行验证并在家系成员中进行检测。结果该家系共4代,现有患者6人,均表现为重度-极重度感音神经性听力下降,先证者男,36岁,6岁时发病,检测到非综合征型常染色体显性聋15型(DFNA15)相关基因POU4F3 c.337C>T(p.Q113*)杂合变异,该家系中其它5例患者(Ⅱ-2、Ⅲ-2、Ⅲ-4、Ⅲ-5和Ⅲ-7)均检测到该杂合变异,而4例听力正常成员(Ⅲ-1、Ⅲ-3、Ⅲ-6、Ⅳ-2)未检测到该变异。根据美国医学遗传学和基因组学学会(ACMG)相关指南对该变异进行致病性评级,变异证据为PVS1+PM2+PP1,属致病变异。结论该家系为一种罕见的由POU4F3基因杂合变异引起的DFNA15型耳聋家系,且可能存在遗传早现现象,POU4F3基因c.337C>T(p.Q113*)变异是该家系耳聋的遗传学病因,可对该家系的遗传咨询提供依据。

Objective To clarify the possible genetic etiology by carrying out a genetic analysis on a family with non-syndromic autosomal dominant progressive hearing loss.Methods Genetic analysis was carried out in the proband using whole-exome sequencing,and the suspected pathogenic sites were verified by Sanger sequencing and detected in family members.Results A heterozygous variant was detected in POU4F3 c.337C>T(p.Q113*)related to non-syndromic autosomal dominant deafness type 15(DFNA15)in the proband.This heterozygous variant was detected in other 5 patients(Ⅱ-2,Ⅲ-2,Ⅲ-4,Ⅲ-5 andⅢ-7)in this family,but the variant was not found in 4 cases(Ⅲ-1,Ⅲ-3,Ⅲ-6 andⅣ-2)with normal hearing.The pathogenicity of this variant was rated according to the relevant guidelines of the American College of Medical Genetics and Genomics(ACMG).The evidence of the variant was PVS1+PM2+PP1,which was a pathogenic variant.Conclusion This family is a rare family with DFNA15 caused by heterozygous variation of POU4F3 gene,and there may be genetic anticipation.The c.337C>T(p.Q113*)variant in POU4F3 gene is the genetic etiology of deafness in this family,which can provide a basis for genetic counseling in this family.