Genetic characteristic analysis of slight-to-moderate sensorineural hearing loss in children
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摘要: 目的 分析儿童轻中度感音神经性听力损失患者遗传因素及其表型特征。方法 纳入中国聋病基因组计划项目轻中度感音神经性听力损失患者及其父母。通过纯音测听、行为测听、听性稳态反应(ASSR)、听性脑干反应(ABR)阈值、畸变耳声发射(DPOAE)等听力学检测确定患者听力水平, 并按2022年美国医学遗传学与基因组学会(ACMG)听力损失的临床实践指南进行听力分级评估。对先证者的外周静脉血进行全外显子组测序(WES)、耳聋基因Panel检测等基因检测方法, 并对其父母行Sanger测序以验证变异位点。结果 纳入134例患者均为儿童期发病, 听力学检查提示均为双侧对称性轻中度感音神经性听力损失。134例患者中, 有听力损失家族史29例(21.6%), 其余均为散发患者。66例(49.3%)有明确遗传致病基因。共计检出11种致病基因, 其中 GJB2基因致病34例(51.5%), STRC基因10例(15.1%), MPZL2基因6例(9.1%), USH2A 基因5例(7.6%)。 GJB2作为轻中度听力损失检出最常见的基因, 其中c.109G>A纯合共检出16例(47.1%), 其次为c.109G>A复合杂合9例(26.5%)。结论 本研究通过分析134例儿童轻中度感音神经性听力损失患者遗传学特征, 发现其以隐性遗传为主, 最常见的基因为 GJB2, 其次为STRC、 MPZL2、 USH2A 等基因。为未来儿童轻中度听力损失的早期筛查及发现提供了重要遗传理论参考。Abstract: Objective To analyze genetic factors and phenotype characteristics in pediatric population with slight-to-moderate sensorineural hearing loss.Methods Children with slight-to-moderate sensorineural hearing loss of and their parents, enrolled from the Chinese Deafness Genome Project, were studied. Hearing levels were assessed using pure tone audiometry, behavioral audiometry, auditory steady state response(ASSR), auditory brainstem response(ABR) thresholds, and deformed partial otoacoustic emission(DPOAE). Classification of hearing loss is according to the 2022 American College of Medical Genetics and Genomics(ACMG) Clinical Practice Guidelines for Hearing Loss. Whole exome sequencing(WES) and deafness gene Panel testing were performed on peripheral venous blood from probands and validations were performed on their parents by Sanger sequencing.Results All 134 patients had childhood onset, exhibiting bilateral symmetrical slight-to-moderate sensorineural hearing loss, as indicated by audiological examinations. Of the 134 patients, 29(21.6%) had a family history of hearing loss, and the rest were sporadic patients. Genetic causative genes were identified in 66(49.3%) patients. A total of 11 causative genes were detected, of which GJB2 was causative in 34 cases(51.5%), STRC in 10 cases(15.1%), MPZL2 gene in six cases(9.1%), and USH2A in five cases(7.6%).The most common gene detected in slight-to-moderate hearing loss was GJB2, with c. 109G>A homozygous mutation found in 16 cases(47.1%) and c. 109G>A compound heterozygous mutation in 9 cases(26.5%).Conclusion This study provides a crucial genetic theory reference for early screening and detection of mild to moderate hearing loss in children, highlighting the predominance of recessive inheritance and the significance of gene like GJB2, STRC, MPZL2, USH2A .
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Key words:
- children /
- slight-to-moderate hearing loss /
- genetic diagnosis
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表 1 134例儿童轻中度SNHL患者的基本信息及临床特征
患者特征 数量/例 占比/% 性别 男 69 51.5 女 65 48.5 家族史 无 105 78.4 有 29 21.6 发病年龄 先天(≤6个月) 44 32.8 语前(6个月~3岁) 10 7.5 语后(＞3岁) 80 59.7 听损程度(500~4 000 Hz) 轻微 5 3.7 轻度 52 38.8 中度 77 57.5 基因检测 全外显子组测序 63 47.0 耳聋Panel检测 65 48.5 其他 6 4.5 
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表 2 34例 GJB2 致病患者双等位基因型
GJB2致病基因型 数量/例 占比/% GJB2纯合 20 58.8 c.109G>A+c.109G>A 16 47.1 c.235delC+c.235delC 2 5.9 c.299_300delAT+c.299_300delAT 1 2.9 c.176_191del+c.176_191del 1 2.9 GJB2复合杂合 14 41.2 c.109G>A+c.235delC 5 14.7 c.235delC+c.299_300delAT 3 8.8 c.109G>A+c.427C>T 2 5.9 c.109G>A+c.176_191del 1 2.9 c.109G>A+c.299_300delAT 1 2.9 c.176_191del+c.235delC 1 2.9 c.299_300delAT+c.511_512insAACG 1 2.9
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