75649例新生儿耳聋基因筛查及确诊者随访结果分析

A Follow-up Study of 75649 Newborn Genetically Screened for Deafness and Patients with Confirmed Deafness

目的分析北京地区大样本新生儿耳聋基因筛查的突变情况、纯合/复合杂合突变者(确诊者)的听力学特点及干预情况。方法研究对象为2012年4月~2014年4月在北京地区出生的新生儿75649例,均接受了新生儿耳聋基因筛查,包括4基因9个位点:GJB2基因(c.35delG、c.176_191del16、c.235delC、c.299_300delAT)、SLC26A4基因(c.919-2A>G、c.2168A>G)、线粒体12SrRNA基因(m.1555A>G、m.1494C>T)和GJB3基因(c.538C>T)。分析阳性检出率及等位基因检出率,并对纯合/复合杂合突变者(确诊者)进行随访,分析新生儿听力筛查结果、听力损失程度,干预时间及干预效果。结果总体阳性检出率4.51%(3412/75649),其中GJB2基因最高,为2.419%(1830/75649),其次由高到低分别为SLC26A4基因1.520%(1150/75649)、GJB3基因0.328%(248/75649)、线粒体12SrRNA 0.184%(139/75649)及双基因杂合突变0.059%(45/75649)。关于等位基因突变检出率,GJB2基因中c.235delC最高,为0.91%(1380/151298),SLC26A4基因中c.919-2A>G最高,为0.67%(1010/151298)。对纯合/复合杂合突变者17例进行随访,成功15例,失访2例。成功的15例中,新生儿听力筛查双耳未通过占80%(12/15),双耳通过为20%(3/15);15例均为感音神经性听力损失,其中重度及极重度66.67%(10/15),中度20%(3/15),轻度13.33%(2/15)。15例中接受听力干预13例,助听器初次干预月龄中位数为6个月,人工耳蜗干预月龄中位数为18个月。15例中就读于正常小学或正常幼儿园14例(93.33%)。结论本研究的主要突变基因为GJB2基因及SLC26A4基因;c.235delC和c.919-2A>G为主要突变位点。新生儿耳聋基因筛查确诊者均有不同程度的听力损失,早期干预效果好,提示新生儿耳聋基因筛查值得推广;新生儿听力筛查通过的耳聋基因筛查确诊者,尤其需要临床关注。

Objective To report mutations detected in a large-scale newborn deafness genetic screening program in Beijing,as well as the audiological characteristics and intervention in patients with confirmed homozygous/compound heterozygous mutations.Methods The study included 75,649 babies born in Beijing from April 2012 to April 2014.All subjects underwent newborn deafness genetic screening covering 9 variants in 4 genes,i.e.the GJB2 gene(c.35delG,C.176_191del16,c.235delC,c.299_300delAT),SLC26A4 gene(c.919-2A>G,c.2168A>G),Mt12SrRNA(m.1555A>G,m.1494C>T)and GJB3 gene(c.538C>T).Cases with homozygous/compound heterozygous mutations were followed up on their hearing.The results of universal newborn hearing screening(UNHS),severity of hearing loss,time and out-comes of intervention were reported.Results The overall mutation detection rate was 4.51%(3412/75649),with the GJB2 gene being the most frequently involved at 2.419%(1830/75649),followed by the SLC26A4 gene at 1.520%(1150/75649),the GJB3 gene at 0.328%(248/75649),Mt12SrRNA at 0.184%(139/75649)and double heterozygous mutations at 0.059%(45/75649).Regarding the alleles involved,c.235delC was the most common mutation of the GJB2 gene at 0.91%(1380/151298),and c.919-2A>G the most common mutation of the SLC26A4 gene at 0.67%(1010/151298).Seventeen patients were found to have homozygous/compound heterozygous mutations and 2 were lost to follow up.Among the 15 cases successfully followed up,20%passed the UNHS and 80%failed screening and were referred,all found to have sensorineural hearing loss of severe to profound 66.67%(10/15),moderate 20%(3/15)or mild 13.33%(2/15)severities.Of the 15 patients,13 were received hearing intervention,at the median age of 6 months for hearing aid and 18 months for cochlear implantation;and 14(93.33%)were enrolled in normal primary schools or kindergartens.Conclusion GJB2 and SLC26A4 gene mutations are most commonly detected in newborn deafness genetic screening in Beijing with c.235delC and c.919-2A>G being among the most common variants.In babies confirmed of hearing loss,early intervention is effective,supporting the value of adoption of newborn deafness genetic screening.Babies passing UNHS while showing homozygous/compound heterozygous mutations on genetic screening especially require adequate attention.