携带线粒体DNA致病突变家庭的聋病遗传咨询特征分析  

Interpretation of pathogenic variants and genetic counselling for mitochondrial hearing loss

作　　者：关静[1] 李进[1] 吴萧男 高云[1] 王洪阳[1] 王秋菊[1] Guan Jing;Li Jin;Wu Xiaonan;Gao Yun;Wang Hongyang;Wang Qiuju(Senior Department of Otolaryngology Head and Neck Surgery,the Sixth Medical Center of PLA General Hospital,National Clinical Research Center for Otolaryngologic Diseases,Beijing 100853,China)

机构地区：[1]解放军总医院第六医学中心耳鼻咽喉头颈外科医学部、国家耳鼻咽喉疾病临床医学研究中心,北京100853

出　　处：《中华耳鼻咽喉头颈外科杂志》2023年第11期1077-1085,共9页Chinese Journal of Otorhinolaryngology Head and Neck Surgery

基　　金：国家自然科学基金(82271171,81900951,81830028,82222016)。

摘　　要：目的分析携带线粒体DNA致病突变家庭的聋病遗传咨询特征及其临床意义。方法“中国聋病基因组计划(CDGP)”项目中以“聋病遗传咨询”为主诉家庭,采用靶向捕获技术对线粒体基因组、聋病相关核基因进行高通量测序,排除了明确已知耳聋核基因突变后筛选出携带线粒体DNA致病突变的首诊个体,对其进行家系资料收集、绘制家系图谱,完善相关人员听力学检测及家系内候选基因变异的验证分析。结果在513个咨询家庭中共发现20个明确携带线粒体DNA致病变异家庭,首诊个体中有16例耳聋先证者和4例无症状咨询者,分别携带MT-RNR1、MT-TS1和MT-TL1三个基因的9种突变:m.1095T>C、m.1310C>T、m.1494C>T、m.1555A>G、m.3243A>G、m.7445A>G、m.7505T>C、m.7510T>C和m.7511T>C。MT-RNR1和MT-TS1基因以同质突变为主,MT-TL1基因为异质突变,先证者以中度以上的斜坡型或平坦型感音神经性听力损失为主,也有显著的表型异质性,其中m.7445A>G同质突变患者听力呈明显进行性下降,m.7505T>C同质突变听力损失呈谷型,携带m.1095T>C个体的聋病外显率较低,携带m.3243A>G异质突变的患者可表现为非综合征型耳聋或糖尿病伴耳聋综合征。结论携带线粒体DNA致病突变个体及其母系家庭成员发生耳聋的风险较高,但携带者的发病年龄、听力损失程度及外显率等存在显著差异,在遗传咨询中需要明确排除核基因可疑致病变异并分析携带者的线粒体DNA突变比例,同时完善首诊个体及其母系家庭人员的听力检测,以咨询家庭为单位进行线粒体突变表型-基因型特征分析,有利于线粒体耳聋遗传咨询个性化的临床决策。Objective To analyze the genetic counseling characteristics and interpretation of pathogenic variants for mitochondrial hearing loss.Methods We analyzed a total of 513 unrelated families from Chinese Deafness Genome Project(CDGP),in which previous gene testing had found no pathogenic mutations with hearing loss(HL)related to the nuclear genes.We used targeted testing and complete mtDNA sequencing for the families′available members.Results Among the first individuals of the families to be tested,20 cases(16 probands and 4 normal hearing consultants)were discovered with variants in mtDNA,including m.1095T>C,m.1310C>T,m.1494C>T and m.1555A>G in MT-RNR1,m.7445A>G,m.7505T>C,m.7510T>C and m.7511T>C in MT-TS1,and m.3243A>G in MT-TL1.We identified MT-RNR1 and MT-TS1 variants occurred as homoplasmic changes,while MT-TL1 variants occurred as heteroplasmic changes.Most mitochondrial hearing loss were characterized by slope or flat moderate to profound sensorineural HL.HL associated with the mtDNA pathogenic variant was variable onset age,severity and audiometric configuration.The penetrance for HL in individuals with the m.1095T>C variant might be low.Progression in the severity of HL was caused by the m.7445A>G pathogenic variant and the patients with m.7505T>C had cookie bite HL.MT-TL1 m.3243A>G was a common spot for pathogenic variants associated with nonsyndromic HL as well as syndromic HL with diabetes mellitus.Conclusions Individuals with the mtDNA variants and their maternal relatives have a higher risk of HL and phenotypic heterogeneity in the age of onset,progression,and level of HL.The medical history should include review of any audiological testing of the probands and their family members on a maternal mtDNA background.The process of genetic evaluation needs rule out nuclear gene mutations and analyzes the genetic load of mitochondrial pathogenic variants in the probands or consultants.In these cases,we rely on clinical and genetic evaluation molecular analysis to appropriately counsel families for whom an exa

关 键 词：DNA 线粒体 线粒体耳聋 遗传咨询 MT-RNR1基因 MT-TS1基因 MT-TL1基因 

分 类 号：R764.43[医药卫生—耳鼻咽喉科]