非综合征型听力损失中缝隙连接蛋白β-6变异的临床和遗传学特征：一例家系评估及计算机分析的病例报告

文献信息

中文摘要

非综合征型感音神经性听力损失（NSHL）表现出显著的遗传异质性，其致病变异的鉴定仍然是一项重要挑战。缝隙连接蛋白β-6（GJB6）表达于包括内耳感觉上皮在内的多种组织，对听觉功能至关重要。尽管GJB6大片段缺失已被充分表征，但单核苷酸变异（SNV）报道较少，其致病意义仍不明确。在本研究中，我们通过全外显子组测序在一名来自近亲婚配家庭的32岁伊朗女性中鉴定出一个新的GJB6纯合错义变异NM_001110219.3:c.446C>T（p.Ala149Val），并通过Sanger测序确认。该患者表现为语前双侧感音神经性听力损失，无其他表型或综合征特征。她于2025年3月在伊朗德黑兰被转诊至医学遗传学实验室。计算机预测、哺乳动物保守性及结构建模提示该替换可能破坏GJB6的正常功能。为了解该发现的意义，我们回顾了GJB6中所有已报道的SNV，共鉴定出47例患者中的20个不同变异，大多数突变聚集在细胞外环1、细胞质环、跨膜结构域3和细胞外环2。这些结果扩展了GJB6的突变谱，并强调了其在NSHL发病机制中的关键作用。总之，本研究首次全面报道了GJB6中的SNV，并支持在遗传性听力损失的遗传结构中对其进行进一步研究。

英文摘要

Non-syndromic sensorineural hearing loss (NSHL) exhibits substantial genetic heterogeneity, and the identification of its causative variants remains an important challenge. The gap junction protein β-6 (GJB6), expressed in multiple tissues including the sensory epithelium of the inner ear, is essential for auditory function. Although large GJB6 deletions are well characterized, single-nucleotide variants (SNVs) have been reported infrequently, and their pathogenic significance remains insufficiently defined. In this study, we identified a novel homozygous missense variant in GJB6, NM_001110219.3:c.446C>T (p.Ala149Val), through whole-exome sequencing and confirmed it by Sanger sequencing in a 32-year-old Iranian female from a consanguineous family, presenting with prelingual bilateral sensorineural hearing loss without any additional phenotypes or syndromic features. She was referred to the Medical Genetics Laboratory in Tehran, Iran, in March 2025. In silico predictions, mammalian conservation, and structural modeling suggest that this substitution may disrupt normal GJB6 function. To contextualize this finding, we reviewed all reported SNVs in GJB6, identifying 20 distinct variants in 47 patients, with most mutations clustering in the extracellular loop 1, cytoplasmic loop, transmembrane domain 3, and extracellular loop 2. These results expand the mutational spectrum of GJB6 and highlight its critical role in NSHL pathogenesis. Collectively, this study presents the first comprehensive report of SNVs in GJB6 and supports their further investigation in the genetic architecture of hereditary hearing loss.