常染色体显性遗传性听神经病家系全外显子组测序分析

目的：在多年围绕1个常染色体显性遗传性非综合征型听神经病家系开展系统分子遗传学研究的基础上，进一步探讨该家系耳聋的致病机制，以期发现新的听神经病致病基因和突变位点。方法：对3例耳聋患者和1例配偶进行全外显子组测序，初步筛选出与家系耳聋相关的候选致病基因。采用PCR-Sanger测序法，检测上述候选基因变异是否与家系表型共分离。最后，以50例与研究家系无关的听力正常人为对照，检测候选致病突变在正常群体中的突变频率和SNPs遗传多态性。结果：全外显子测序分析得到41个候选致病基因突变；用PCR-Sanger测序法对核心家系的9名成员和2名家系外听力正常人进行验证，仅发现1个基因突变（ALOX15B 7942797 C>T）与家系耳聋表型共分离。选取50例家系外正常对照的DNA样本对ALOX15B基因进行PCR扩增和序列分析，结果显示有2例听力正常人也检测到该基因的同一变异，提示该变异为SNPs遗传多态性。结论：对核心家系成员的全外显子组测序分析和Sanger测序法验证未发现有意义的突变位点，排除了该家系耳聋由基因编码区突变及Indels致病的可能性。

Whole-exome sequencing analysis in a Chinese pedigree with autosomal dominant auditory neuropathy

Objective: On the basis of previous systematic investigation on a Chinese pedigree with dominantly inherited auditory neuropathy, we aims to further search the deafness-causing genes (mutations) involved in this family. Methods: Whole-exome sequencing was conducted in three affected members and one spouse to determine the candidate genes related to the pedigree, and cosegregation analysis was performed on other members of the family. Finally, fifty normal-hearing individuals acting as controls were recruited for candidate variant detection. Results: A total of 41 variations were identified by whole-exome sequencing analysis. These variations were verified in the kernal pedigree members and 2 normal-hearing individuals by PCR-Sanger sequencing. The results showed that there was only ALOX15B gene co-segregated with the phenotype of the family. This gene mutation, however, was also detected in 2 of 50 normal-hearing individuals, which excluded the causative effect of ALOX15B mutation in this family. Conclusion:Whole-exome sequencing combined with Sanger sequencing does not reveal novel gene mutation in this family, which excludes the causative effects of Indels or mutations in coding sequence.