新生儿听力及基因联合筛查临床实践及筛查模式研究

An Clinical Research on Newborn Hearing Concurrent Genetic Screening in 106,513 Neonates

目的分析新生儿听力及基因联合筛查的全国多中心数据,探讨建立新生儿听力及基因联合筛查临床推广的标准模式。方法 2006年12月至2012年12月,全国13个省市出生的106,513例新生儿作为研究对象,进行听力及常见致聋基因的同步筛查。其中,听力筛查方法采用OAE和AABR两步筛查,采集新生儿脐带血或足跟血进行常见耳聋基因突变热点筛查,突变筛查方法包括测序、限制性核酸内切酶检测、四引物扩增受阻PCR试剂盒检测和质谱分析,所有阳性样本通过直接测序方法进行验证和确认,对联合筛查结果进行统计分析,并建立新生儿听力及基因联合筛查的标准化模式与规范。结果 106,513例新生儿中,听力筛查通过率为91.48%(97,433/106,513),未通过率为8.52%(9,080/106,513)。基因筛查突变率为:GJB2 c.235delC未通过25例,GJB2 c.235delC携带者1647例,占1.55%(1647/106,513);SLC26A4 c.919-2 A>G未通过11例,SLC26A4 c.919-2 A>G携带者1203例,占1.16%(1203/103,798);MTRNR1突变m.1555A>G未通过157例,占0.15%(157/106,064),m.1494C>T未通过12例,占0.01%(12/83,299);四个筛查位点未通过共205例,携带者共2850例,基因筛查阳性者共3055例。其中,GJB2 c.235delC突变未通过的25例中,听力筛查未通过21例,4例听力初筛通过;SLC26A4 c.919-2 A>G突变未通过的11例中,听力筛查未通过7例,4例听力初筛通过;MTRNR1突变未通过169例中,m.1555A>G突变者听力筛查通过147例,占93.6%(147/157),m.1494C>T突变者听力筛查通过10例,占83.3%(10/12),MTRNR1总体突变者中听力筛查通过157例,占92.9%(157/169)。结论对新生儿进行听力及基因联合筛查具有临床可行性,对筛查结果的联合解读可以在听力筛查的基础上提供更多迟发性或潜在耳聋的遗传信息,为推广新生儿听力及基因联合筛查提供了多中心临床研究证据,并通过临床实践建立了聋病防控新模式。

Objective To analyze the data of newborn hearing concurrent genetic screening in China, and to establish a model of hearing combined genetic screening. Methods Between December 2008 and December 2012, a total of 106,513 new- horns from 13 provinces in China were included in the study. We analyzed the universal newborn hearing screening and the newly developed genetic screening results. All newborn babies received a two step hearing screening protocol of OAEs or AABRs. Blood samples were collected with a universal newborn genetic screening card. Three common genes, MTRNR1, GJB2and SLC26A4 were screened with a standard protocol. Results Among all the 106,513 neonates, 91.48% （97,433/106, 513） passed the first-step hearing screening, 3.41% （3638/106,513） passed on one side, and 5.11% （5,442/106,513） were bilat- erally referred. Gene screening identified 3,055 individuals with one or two mutant alleles and the carrier rate was 2.87% （3, 055/106,513） among the entire newborn population. The risk for hearing loss was 100% （33/33） for those carrying causative GJB2 or SLC26A4 mutations （homozygotes or compound heterozygotes）. A total of 169 newborns were found to have MTRNR1 mt. 1555A〉G or mt. 1494C〉T pathogenic mutation, who would suffer from hearing loss upon exposure to aminoglycoside drugs. Conclusions This study indicates that conventional newborn hearing screening can be improved by adding a genetic compo- nent. Genetic testing complements the current newborn hearing screening program and provides additional insights beyond what conventional audiological tests can provide, thus significantly advancing the current practice to improve the newborn hear- ing screening as a means of early discovery of genetic risk factors.