中国人群MYO15A基因同义突变引起剪接异常导致的非综合征型耳聋分析

Analysis of non-syndromic hearing loss caused by splicing abnormalities due to a synonymous mutation of MYO15A gene in a Chinese population

目的对一个遗传性非综合征型耳聋家系的临床特征进行分析并鉴定其致聋基因突变,同时在大规模耳聋人群队列中对鉴定出的致病性突变致中国人群耳聋的特征进行分析。方法完善家系成员的问卷调查、听力学检查、体格检查等临床检查,同时采集血液样本,通过耳聋相关基因的大规模平行测序(MPS)和生物信息学分析进行致病基因鉴定。总结及分析鉴定出的致病性突变在中国耳聋基因研究战略联盟(CDGC)耳聋数据库中的检出情况。结果在一个早发性极重度感音神经性耳聋家系中鉴定出MYO15A基因NM_016239.4:c.8182C>G(p.Arg2728Gly)/c.9861C>T(p.Gly3287=)复合杂合突变,为该家系耳聋患者的致聋原因。其中MYO15A基因c.9861C>T(p.Gly3287=)同义突变通过改变剪接导致基因功能缺陷,其在中国广西壮族人群中次要等位基因频率为0.2%(3/1438),在其他人群及公共数据库中均未检出。结论研究确定了MYO15A基因c.9861C>T(p.Gly3287=)在中国非综合征型耳聋患者中的致病性,该突变在中国广西壮族自治区富集明显。通过研究强调了在致病基因鉴定时,高频与同义突变并非过滤的绝对指标,尤其是在某些地区富集格外明显的突变,应格外注意。

Objective To analyze the clinical phenotype of a family with hereditary non-syndromic deafness and to identify the deafness-causing gene mutation,and to analyze the characteristics of deafness caused by one of the identified pathogenic synonymous mutation in Chinese population in a large scale deaf population cohort.Methods The clinical examinations such as questionnaire survey,audiological test and physical examination of the family members were completed,and their blood samples were collected for targeted genomic enrichment with massively parallel sequencing(MPS)and bioinformatics analysis to identify the causative gene.The identified pathogenic mutation detected in Chinese Deafness Genetics Consortium(CDGC)were summarized and analyzed.Results The compound heterozygous mutations of MYO15A gene NM_016239.4:c.8182C>G(p.Arg2728Gly)/c.9861C>T(p.Gly3287=)were identified as the cause of deafness in this family with early-onset severe sensorineural deafness,among them,MYO15A gene c.9861C>T(p.Gly3287=)synonymous mutation led to gene dysfunction by altering splicing.The minor allele frequency was 0.2%(3/1438)in the Zhuang population in Guangxi,China,but was not detected in other populations or public databases.Conclusion The pathogenicity of MYO15A gene c.9861C>T(p.Gly3287=)in non-syndromic deafness patients in China has been confirmed in this study.This mutation is obviously enriched in Guangxi Zhuang Autonomous Region,China.It is emphasized that high-frequency and synonymous mutations are not absolute indicators of filtration in the identification of disease-causing genes,and extra care should be taken especially for the mutation with especially obvious enrichment in some regions.