一个四代遗传性耳聋家系POU4F3和PDZD7基因突变致病性研究

Pathogenic POU4F3 and PDZD7 Mutations in a Four Generation Family with Hereditary Hearing Loss

目的分析一个四代遗传性耳聋家系的临床特征及致病基因鉴定。方法对该家系成员进行问卷调查、听力学检查、视觉系统检查、体格检査等,应用靶向富集大规模平行测序(targeted genomic enrichment with massively parallel sequencing,TGE+MPS)和生物信息学分析进行致病基因鉴定。结果该家系耳聋患者听力表型差异明显且存在两种遗传模式,通过二代测序鉴定出两个致病基因——POU4F3:NM_002700.3:c.976A>G(p.Arg326Gly)和PDZD7:NM_024895.4:c.490C>T(p.Arg164Trp)突变与该家系耳聋表型有关,Sanger测序验证两基因突变符合听力表型和基因型共分离,保守性分析显示两基因突变位置氨基酸残基在不同物种中高度保守,蛋白三维结构模拟分析提示两基因突变一定程度上干扰局部二级结构稳定性,影响蛋白亚细胞定位及局部疏水作用。结论本研究在一个耳聋家系中鉴定出POU4F3和PDZD7两个致病基因突变,两基因遗传模式不同,分别为常染色体显性遗传和常染色体隐性遗传。该家系给予我们启示,在具有耳聋家族史的同一家系中有可能存在多基因致病情况,当我们发现一个基因的致病性突变时,耳聋基因诊断可能并没有结束,建议条件允许时,临床耳聋基因诊断应尽量选择高通量检测技术平台以避免漏诊。

Objective To report clinical characteristics and identify the causative genes in a four-generation family with hereditary hearing loss.Methods The family was investigated by questionnaires,audiologic tests,visual system examinations and physical examinations.Causative genes were identified by targeted genomic enrichment with massively parallel sequencing(TGE+MPS)and bioinformatics analysis.Results In this family,phenotype of hearing loss varied with significant differences and two different kinds of hereditary patterns existed.Two pathogenic mutations,POU4F3:NM_002700.3:c.976A>G(p.Arg326Gly)and PDZD7:NM_024895.4:c.490C>T(p.Arg164Trp)were identified by MPS in the family.Sanger sequencing confirmed that the mutations were co-segregated with the hearing loss in this family.Conservation analysis showed that the amino acid residues of the mutations were highly conserved in different species.Three dimensional protein structures showed that the mutations disturbed the stability of the local secondary structure to some extent and affected the protein subcellular localization and local hydrophobicity.Conclusion Mutations of the POU4F3 and PDZD7 genes were identified in a four-generation family with hereditary hearing loss,which were transmitted in autosomal dominant inheritance and autosomal recessive inheritance respectively.This family enlightens us that there may be multiple genes in one family with family history of deafness.Finding pathogenicity mutations of one gene may not signal the end of genetic diagnosis of deafness.It is suggested that high-throughput technology platform should be applied for clinical gene diagnosis of deafness to avoid missed diagnosis.