GJB2 c.109G>A（p.Val37Ile）相关听力损失的不完全外显率与异质性表型
Incomplete penetrance and heterogeneous phenotypes of hearing loss associated with GJB2 c.109G>A (p.Val37Ile).
文献信息
| PMID | 42967444 |
|---|---|
| 原文 | 在 PubMed 查看原文 ↗ |
| 发表日期 | 2026 |
| 作者 | Anpeng Fu |
| 作者单位 | Medical Genetic Center, Guangdong Women and Children Hospital, Guangzhou, Guangdong, 510010, China; Guangzhou Medical University, Guangzhou, Guangdong, 510010, China. |
| 期刊 | International journal of pediatric otorhinolaryngology |
| SCI 分区 | Q2 |
| IF | 1.7 |
| 研究类型 | 综述 Meta · 临床 |
| 所属专科 | 耳科 |
中文摘要
背景： GJB2 c.109G>A（p.Val37Ile）是东亚人群中常见的错义变异，具有不完全外显率和异质性听力表型。本分析评估了其外显率及基因型-表型相关性。
方法： 我们检索了PubMed、Web of Science、CBM、CNKI和万方数据截至2025年12月1日的文献，纳入可提取GJB2 c.109G>A（p.Val37Ile）与听力表型数据的研究。采用随机效应模型估计合并比例及95%CI；按年龄、基因型和严重程度进行亚组分析，并进行敏感性分析和发表偏倚分析。
结果： 共纳入31项研究。研究人群包含604,999名个体；外显率分析纳入1211名双等位基因携带者，其中622例存在听力损失。合并外显率为55.04%（95%CI，43.39%-66.16%），异质性显著（I2=89.4%，P<0.0001）。外显率在各年龄组间无显著差异（P=0.2523），纯合与复合杂合基因型之间亦无显著差异（60.70% vs 56.26%，P=0.6838）。听力损失以轻度（62.52%）或中度（28.35%）为主，儿童分布相似（64.41%和26.57%）。留一法分析显示估计值稳定。排除4项报告0%或100%外显率的研究后（保留27项），合并外显率为50.79%（95%CI，38.81-62.67%），结果相似。各年龄组间未检测到外显率的统计学显著差异（P=0.2523）。然而，成人亚组样本量小，且多数研究为横断面设计；因此，不能排除年龄依赖性外显率，包括迟发性或进展性听力损失。Egger's和Begg's检验未显示发表偏倚。
结论： GJB2 c.109G>A（p.Val37Ile）表现为不完全外显率和可变听觉表型。尽管在年龄和基因型亚组间未观察到显著的外显率差异，但统计效能有限及横断面设计无法排除年龄依赖性效应。听力损失以轻至中度为主。合并估计值对敏感性分析稳健。这些发现支持谨慎的临床解读、基因型特异性咨询和长期听力学随访，尤其是对儿童携带者。尽管未发现显著的年龄相关差异，但该结果应被视为不确定而非阴性。鉴于成人数据有限且缺乏纵向随访，不能排除年龄依赖性和迟发性效应。
英文摘要
BACKGROUND: GJB2 c.109G > A (p.Val37Ile) is a common missense variant in East Asian populations with incomplete penetrance and heterogeneous hearing phenotypes. This analysis estimated its penetrance and genotype-phenotype correlation.
METHODS: We searched PubMed, Web of Science, CBM, CNKI and Wan fang Data through December 1, 2025, for studies with extractable GJB2 c.109G > A (p.Val37Ile) and hearing phenotypes. Random-effects models estimated pooled proportions with 95% CIs; subgroup analyses by age, genotype, and severity, plus sensitivity and publication-bias analyses.
RESULTS: Thirty-one studies were included. The study populations comprised 604,999 individuals; 1211 biallelic carriers were included in the penetrance analysis, of whom 622 had hearing loss. Pooled penetrance was 55.04% (95% CI, 43.39%-66.16%), with substantial heterogeneity (I2 = 89.4%, P < 0.0001). Penetrance did not differ significantly across age groups (P = 0.2523) or between homozygous and compound heterozygous genotypes (60.70% vs 56.26%, P = 0.6838). Hearing loss was predominantly mild (62.52%) or moderate (28.35%), with a similar pediatric distribution (64.41% and 26.57%). Leave-one-out analysis showed stable estimates. Excluding four studies reporting 0% or 100% penetrance (27 retained) yielded a similar pooled penetrance of 50.79% (95% CI, 38.81-62.67%). No statistically significant difference in penetrance was detected across age groups (P = 0.2523). However, the adult subgroup was small and most studies were cross-sectional; therefore, age-dependent penetrance, including delayed-onset or progressive hearing loss, cannot be excluded. Egger's and Begg's tests showed no publication bias.
CONCLUSIONS: GJB2 c.109G > A (p.Val37Ile) shows incomplete penetrance and variable auditory phenotypes. Although no significant penetrance difference was observed across age and genotype subgroups, limited statistical power and the cross-sectional design preclude ruling out age-dependent effects. Hearing loss was predominantly mild to moderate. The pooled estimate was robust to sensitivity analyses. These findings support cautious clinical interpretation, genotype-specific counseling, and long-term audiological follow-up, especially for pediatric carriers. Although no significant age-related difference was found, this finding should be considered inconclusive rather than negative. Given limited adult data and lack of longitudinal follow-up, age-dependent and delayed-onset effects cannot be ruled out.