一个常染色体显性遗传性聋家系致病基因鉴定

Identification of the Causative Gene in a Family with Autosomal Dominant Hereditary Hearing Loss

曹婧媛;袁阳;程静;卢宇;杨长亮;阳光;杨慧;周佳;吴雄英;袁慧军;孙艺;

1:中国人民解放军中部战区总医院耳鼻咽喉头颈外科

2:陆军军医大学第一附属医院医学遗传中心

摘要
目的分析常染色体显性遗传性聋家系的听力学及遗传学特征,利用高通量测序和连锁分析技术进行致病基因鉴定。方法采集一个常染色体显性遗传性非综合征型聋家系患者的临床资料,进行耳聋表型和遗传方式的判定并绘制家系图,提取家系成员外周血DNA,首先利用耳聋相关基因靶向测序,对家系先证者进行162个已知耳聋基因的筛查,然后采用全外显子组测序和连锁分析相结合的方法继续寻找致病基因,筛选出候选基因变异位点在家系中进行验证,以明确该家系致病原因。结果该耳聋家系来自河南省,编号为HBSY-012,现存三代共34人,14人诊断为感音神经性聋,为常染色体显性遗传模式,耳聋者发病年龄5~7岁,早期表现为高频听力下降,随年龄增长迅速发展为全频受累的重度或极重度感音神经性聋。对先证者进行已知162个耳聋基因筛查未发现致病突变,家系连锁分析将致病基因定位于第9号染色体q31.1-q31.3区间内(最大LOD值3.6076)。全外显子组测序数据分析显示在连锁分析定位的区间内未发现候选变异,在区间以外筛选出4个候选基因变异位点,候选变异为ANKMY2基因NM_020319:c.822_826del、DDX49基因NM_019070:c.341C>T、DEFB129基因NM_080831:c.284G>T以及EVI5基因NM_005665:c.2399C>T,并对4个候选基因变异位点进行家系验证,结果提示都不是该家系的致病突变。结论该常染色体显性遗传非综合征型聋家系连锁分析将致病基因定位于第9号染色体q31.1-q31.3区间内。耳聋相关基因靶向测序和全外显子组测序均未发现致病突变,考虑该家系致病原因可能为基因的非编码区域的突变或者罕见的CNV/SV所致。
关键词
遗传性聋;常染色体显性;家系;全外显子组测序;连锁分析
基金项目(Foundation):
湖北省自然科学基金面上项目(No.2018CFB719);; 湖北省卫生和计划生育委员会联合基金项目(No.WJ2018H0081)
作者
曹婧媛;袁阳;程静;卢宇;杨长亮;阳光;杨慧;周佳;吴雄英;袁慧军;孙艺;
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