[A follow-up study of abnormal mutation in neonatal deafness gene screening].

Objective: To screen, diagnose and follow up the abnormal mutation in the gene screening of neonatal deafness. Methods: A total of 24161 newborns born in Zhuhai Maternal and Child Health Hospital from February 1, 2015 to January 31, 2008 were screened for hearing and deafness genes, and audiological screening, diagnosis and 1-3 years follow-up were carried out for the newborns with positive gene screening. Results: There were 991 cases of deafness gene mutation (533 males and 458 females), and the rate of abnormal mutation was 4.10%(991/24 161). Among them, 921 cases were single heterozygous mutation, 130 cases were failed in primary hearing screening, 11 cases were failed in secondary hearing screening, 8 cases were abnormal in audiological diagnosis finally. In these 8 cases, 3 were diagnosed as otitis media and passed audiological follow-up after cure, 2 cases of single ear sensorineural injury caused by high-risk factors, passed after close audiological follow-up, and the other 3 cases were closely audiological follow-up while none of them were successfully sequenced. All of them were moderate to severe sensorineural deafness, 1 case was heterozygous mutation at 3 loci of GJB2(c.235delC,c.408C>A,c.134G>A), 1 case was heterozygous mutation at 2 loci of GJB2(c.235delC, c.109G>A), and 1 case was single heterozygous mutation of GJB2(c.235delC). The remaining 913 cases who passed the primary screening, secondary screening or hearing diagnosis were followed up for 1 to 3 years. Three cases of multiple heterozygous mutation were found in gene screening(2 cases were SLC26A4 2168A>G, IVS7-2A>G, 1 case was GJB2 c.176_191del 16bp, c.299_300del AT), all of them passed both primary and secondary hearing screening. In these 3 cases, the final audiological diagnosis was moderate sensorineural deafness in both ears, with no improvement in the follow-up of 1-3 years. There were 9 monogenic homozygous mutations, 7 failed in primary hearing screening, 3 failed in secondary hearing screening and also failed in audiological diagnosis and 1-3 years' audiological follow-up, all of whom were GJB2 c.235 del C homozygous mutations, and one of whom had a definite family history of deafness. The remaining 6 cases of homozygous mutation diagnosed by primary screening, secondary screening or hearing diagnosis were GJB2 c109G>A homozygous mutation, and passed the 1-3 years' hearing follow-up. 58 children with mtDNA mutations, including 2 with 12S rRNA 1494C>T homozygous mutation, 47 with 1555A>G homozygous mutation, and 9 with 1555A>G heterozygous mutation, all passed the primary or secondary hearing screening, and were instructed to ban ototoxic drugs for the whole life, and passed the 1-3 years' hearing follow-up. Conclusions: The audiological follow-up of children with monogenic heterozygous mutations in deafness gene screening is generally normal. In case of abnormality, the influencing factors such as otitis media should be excluded at first. In case of unexplained moderate to severe sensorineural deafness, the whole-gene sequencing should be performed to find possible pathogenic factors. The children with homozygous mutation or compound heterozygous mutation in gene screening, most of whom show different degrees of hearing loss, should be followed up for a long time, and provide parents with scientific and reasonable genetic counseling according to the mutation genes and loci,. The hearing of drug-induced deafness gene carriers is normal after birth. Parents should be advised to strengthen prevention and follow-up is generally enough.目的： 通过对新生儿耳聋基因筛查阳性患儿的听力学筛查、诊断和随访，探讨其听力学转归和随访策略。 方法： 对珠海市妇幼保健院2015年2月1日至2018年1月31日出生或收治的24 161名新生儿进行听力和耳聋基因联合筛查，并对其中基因筛查阳性患儿进行听力学筛查、诊断和1~3年的跟踪随访。 结果： 耳聋基因筛查阳性患儿991例（男533例，女458例），阳性率为4.10%（991/24 161）。其中单杂合突变921例，听力初筛未通过130例，复筛未通过11例，最终听力学诊断异常8例；其中3例确诊为分泌性中耳炎，治愈后听力随访均通过，2例为高危因素引起的单侧感音神经性听力损失，密切听力随访后通过，另外3例1~3年密切听力随访均未通过，均为双耳中、重度感音神经性听力损失，经GJB2全基因测序证实，1例为GJB2基因3位点复合杂合突变（c.235delC突变伴c.408C>A、c.134G>A突变），1例为GJB2基因复合杂合突变（c.235delC突变伴c.109G>A突变），1例仍为GJB2基因单杂合突变（c.235delC突变）；通过初筛、复筛或听力诊断的913例单杂合突变患儿，听力随访1~3年均通过。基因筛查发现复合杂合突变3例（2例为SLC26A4 2168A>G、IVS7-2A>G复合杂合突变，1例为GJB2 c.176_191del 16bp、c.299_300del AT复合杂合突变），听力初筛、复筛均通过，但在随访中出现听力下降，听力学诊断为双耳中度感音神经性听力损失。基因筛查纯合突变9例，听力初筛未通过7例，复筛未通过3例，这3例最终听力学诊断为重度、极重度感音神经性听力损失，听力随访1~3年均未通过（3例均为GJB2 c.235del C纯合突变，其中1例有明确耳聋家族史）；余下通过初筛、复筛或听力诊断的6例纯合突变患儿，均为GJB2 c. 109G>A纯合突变，听力随访1~3年均通过。线粒体基因突变患儿58例，其中12S rRNA 1494C>T同质突变2例、1555A>G同质突变47例、1555A>G异质突变9例，均通过听力初筛或复筛，嘱其终身禁用耳毒性药物，听力随访1~3年均通过。 结论： 耳聋基因筛查单杂合突变患儿听力随访一般正常，如果出现异常需排除中耳炎等影响因素，如果出现无法解释的中重度感音神经性听力损失，建议行全基因测序，寻找可能的致病因素。基因筛查纯合突变或复合杂合突变的患儿，多表现为不同程度的听力损失，均应长期随访，并根据突变基因和位点给家长提供科学合理的遗传咨询。药物性聋基因携带患儿出生后听力正常，嘱家长加强预防，一般随访即可。.