新生儿重症监护病房新生儿耳聋基因致病变异携带者筛查的横断面调查

Carrier screening for pathogenic genes for hearing loss among newborns in a neonatal intensive care unit:A cross-sectional survey

背景我国耳聋发病率高与耳聋基因致病变异的携带率高有关,目前缺乏对NICU新生儿耳聋基因致病变异携带者的筛查数据。目的调查NICU新生儿中耳聋基因GJB2和SLC26A4致病变异的携带率。设计横断面研究。方法纳入2016年1月至2021年12月在复旦大学附属儿科医院NICU住院、入院日龄≤28 d,且出院前完成高通量测序的新生儿,排除生后耳聋相关基因诊断阳性者。从病历系统中截取患儿的性别、胎龄、出生体重;从测序数据库中提取GJB2基因和SLC26A4基因的检测结果、患儿人类表型标准用语信息。携带率(%)=杂合致病或可能致病(P/LP)变异例数/总研究对象人数。检索PubMed、Embase和万方数据库,纳入既往报道中国NICU人群、新生儿人群和孕妇人群中GJB2基因和/或SLC26A4基因P/LP变异携带情况的文献,并行复习。主要结局指标GJB2基因和SLC26A4基因的P/LP变异携带率。结果纳入14924例新生儿,男8587例(57.5%),女6337例,胎龄(35.6±3.7)周,出生体重(2711.7±887.1)g。携带GJB2基因P/LP变异的患儿2009例(13.462%),共检出18种杂合P/LP变异,其中c.109G>A最常见(10.902%),其次为c.235del(1.749%)、c.299_300del(0.409%)、c.176_191del(0.154%)、c.508_511dup(0.074%)和c.257C>G(0.034%)。携带SLC26A4基因P/LP变异的患儿305例(2.044%),共检出31种杂合P/LP变异,携带率最高的6种依次为c.919-2A>G(1.139%)、c.2168A>G(0.181%)、c.1226G>A(0.100%)、c.1229C>T(0.094%)、c.1174A>T(0.080%)和c.1003T>C(0.047%)。结论建议将GJB2基因上的c.109G>A、c.508_511dup和c.257C>G以及SLC26A4基因的c.1003T>C位点纳入NICU新生儿耳聋基因致病变异携带者筛查。

Background The high prevalence of hearing loss in China is associated with a high carrier rate of pathogenic variants in genes for hearing loss.At present,there is a lack of screening data on carriers of pathogenic genes for hearing loss among newborns in neonatal intensive care units(NICU).Objective To investigate the carrier rate of GJB2 and SLC26A4,pathogenic genes for hearing loss,in NICU newborns.Design Cross-sectional survey.Methods Newborns were enrolled in the NICU at Children's Hospital of Fudan University from January 2016 to December 2021,with admission days≤28 d and high-throughput sequencing completed before discharge.Those with positive hearing-loss-associated genetic findings after birth were excluded.The sex,gestational age and birth weight were collected from electronic medical records.The number of cases identified with pathogenic variants in GJB2 and SLC26A4 and the standard terminology of the human phenotype of the children were extracted from the sequencing database.Carrier rate(%)=the number of heterozygous pathogenic or likely pathogenic(P/LP)variants/total number of study subjects.PubMed,Embase,and Wanfang databases were searched.Literature that previously reported the carrier status of the GJB2 gene and/or SLC26A4 gene P/LP mutations in NICU patients,newborns and pregnant women in China were included and reviewed.Main outcome measures Carrier rate of P/LP variants in the GJB2 gene and SLC26A4 gene.Results A total of 14924 neonates were included,including 8587 males(57.5%)and 6337 females,with a gestational age of(35.6±3.7)weeks and a birth weight of(2711.7±887.1)g.A total of 18 heterozygous P/LP mutations were detected in 2009 children(13.462%)carrying P/LP mutations of the GJB2 gene,among which c.109G>A was the most common(10.902%),followed by c.235del(1.749%),c.299_300del(0.409%),c.176_191del(0.154%),c.508_511dup(0.074%)and c.257C>G.There were 305 children(2.044%)carrying P/LP mutations of the SLC26A4 gene.A total of 31 heterozygous P/LP mutations were detected,and the six highest carrier rates were for c.919-2A>G(1.139%),c..2168A>G(0.181%),c.1226G>A(0.100%),c.1229C>T(0.094%),c.1174A>T(0.080%)and c.1003T>C,respectively.Conclusions It is suggested that c.109G>A,c.508_511dup and c.257C>G on the GJB2 gene and c.1003T>C on the SLC26A4 gene should be included in the carrier screening for pathogenic genes for hearing loss among newborns in NICU.