前庭导水管扩大耳聋人群中SLC26A4单等位基因突变的出现率及致病相关性研究

摘要

Objective c.919-2A>G and p.H723R, two hotspot mutations of SLC26A4 were chosen to investigate the detection rate of mono-allelic mutations of SLC26A4 in deaf patients with enlarged vestibular aqueduct (EVA) in Chinese Hans. In comparison with that of normal hearing controls, we evaluated the correlation between EVA and detection of mono-allelic mutations of SLC26A4 in the patients.Methods Sanger sequencing of all exons and flanking splicing sites of SLC26A4 was performed in 121 EVA patients. A microarray-based mutation screening including the c.919-2A>G and p.H723R mutations of SLC26A4 was performed in 3056 normal hearing controls. The direction rates of mono-allelic c.919-2A>G and p.H723R mutations were determined in both groups. The statistical difference was determined using the SPSS software version-19.Results 78 bi-allelic and 12 mono-allelic mutations of SLC26A4 were detected in 121 EVA patients. Mono-allelic c.919-2A>G and p.H723R mutations were detected in 6 and 2 patients, respectively, accounting for a total of 6.61% in the EVA group. In contrast, heterozygous c.919-2A>G and p.H723R mutations were detected in 33 and 9 controls, respectively, accounting for a total of 1.37% in the control group. Fisher’s exact test showed that the detection rate of the mono-allelic c.919-2A>G and p.H723R mutations was significantly different between the EVA group and the control group. Conclusion The incidence of mono-allelic mutations of SLC26A4 in EVA patients was significantly higher than that in normal hearing controls, suggesting that other causative mutations that could not be detected by the regular exon-sequencing method may exist in those patients, which should be further investigated in future studies and be considered in genetic counseling.%目的：以SLC26A4基因热点突变c.919-2A>G和p.H723R为对象，研究SLC26A4基因单等位基因突变在中国汉族非综合征大前庭导水管（enlarged vestibular aqueduct，EVA）耳聋人群中的出现频率，并通过与正常听力人群的比较评估该疾病SLC26A4单等位基因突变的检出与疾病发生的相关性。方法通过Sanger测序对121例EVA耳聋患者进行SLC26A4基因的全部外显子及剪切位点的序列筛查，经耳聋基因突变检测芯片对3056例正常听力对照进行热点突变筛查，分别确定c.919-2A>G和p.H723R单杂合突变在两组人群中的出现频率，利用统计软件SPSS 19.0分析其统计学差异。结果121例EVA耳聋患者中有78例样本检出SLC26A4基因双等位基因突变，12例样本检出单等位基因突变，其中6例为c.919-2A>G单杂合突变，2例为p.H723R单杂合突变，共占患病人群的6.61%；3056例正常听力对照中发现33例c.919-2A>G和9例p.H723R单杂合突变，占对照人群的1.37%；Fisher’s exact检验显示，SLC26A4基因c.919-2A>G和p.H723R单杂合突变的出现率在EVA耳聋组与正常对照组之间存在显著差异（P=0.001）。结论 SLC26A4单等位基因突变在EVA耳聋患者中的出现率显著高于正常对照人群，提示携带SLC26A4单等位基因突变的EVA耳聋患者可能存在无法用常规外显子测序方法所检出的其它致病基因突变，需进一步研究，并在相关遗传咨询中加以注意。