一个遗传性耳聋伴前庭功能障碍家系的分子病因学研究

Analysis of gene mutation in a hereditary hearing loss family associated with vestibular dysfunction

目的:对1个遗传性耳聋伴前庭功能障碍家系进行遗传方式、表型特征及致病基因的分析,以研究其分子病因。方法 :对门诊1例遗传性聋伴眩晕患者进行家系调查、病史收集及相应的听力学和前庭功能检查。利用目标基因捕获和大规模平行测序技术,对家系先证者进行可能致病突变筛查,包括靶向104种与遗传性听力损失相关的基因和3个micro RNA分子。进一步对获得的候选突变基因进行编码区序列验证分析。结果:目标基因捕获测序结果发现先证者COCH基因第11外显子上存在c.1458C>G(p.T352S)的杂合突变。进一步对家系中所有患者和有血缘关系的正常个体进行了遗传共分离分析,发现该杂合突变在该家系中仅有Ⅰ2、Ⅱ1、Ⅱ5、Ⅱ9、Ⅱ13和Ⅳ1存在相同的杂合突变,而Ⅱ11和Ⅲ1表现为该突变的纯合子,表明该杂合突变不存在共分离现象,因此可以排除其为该家系致病突变的可能性。对先证者Ⅲ14COCH基因全部12个外显子的序列测定结果未发现其他突变。结论:此家系为常染色体显性遗传性非综合征型耳聋伴前庭功能障碍,但初步筛查结果未发现已知耳聋相关基因,包括COCH基因的可疑致病突变。因此,该家系的分子病因可能存在一新基因的突变。

Objective：To study the molecular etiology of a hereditary hearing loss family associated with vestibular dysfunction by analyzing genetic pattern,phenotypic characteristics and pathogenic gene. Methods：Clinical data（medical history,audiological and vestibular function examination,as well as imaging examination） were collected. By target gene capture and massively parallel sequencing technologies,104 species and genes related to hereditary hearing loss and 3 micro RNAs in probands of the pathogenic mutation were screened. Furthermore,we analyzed the gene coding region sequence of candidate mutations. Results：C.1458CG（p.T352S） heterozygous mutations were found in the exon 11 of the COCH gene. Ⅰ2, Ⅱ1, Ⅱ5, Ⅱ9, Ⅱ13and Ⅳ1showed the same heterozygous mutation. Ⅱ11and Ⅲ1showed that the mutation was homozygous for this mutation,which means that there was no cosegregation,therefore,the possibility of pathogenic mutation in the family could be eliminated. No other mutations were found in the sequence of all 12 exons of the Ⅲ14COCH gene. Conclusion：This family has an autosomal dominant disorder associated with vestibular dysfunction. However,the initial screening results were not found to be associated with the known deafness genes,including the COCH gene. Therefore,the molecular etiology of this family may be a new gene mutation.