Hearing loss (HL) is clinically and genetically heterogeneous disorder and is the most frequent occurring sensory deficit in humans. This study was conducted to decipher the genetic cause of HL occurring in two large consanguineous Pakistani families (GCNF-01, GCNF-03). Family history and pure tone audiometry of both families suggested prelingual HL, while the affected individuals of GCNF-01 also had low vision and balance problems, consistent with cardinal features of Usher syndrome type I (USH1). Exome sequencing followed by segregating analysis revealed a novel splice site variant (c.877-1G > A) of USH1C occurring with USH1 phenotype in family GCNF01. While the affected individual of family GCNF-03 were homozygous for the c.716 T > A, p.(Val239Asp) previously reported pathogenic variant of SLC26A4. Both variants have very low frequencies in control database. In silico mutagenesis and 3-dimensional simulation analyses revealed that both variants have deleterious impact on the proteins folding and secondary structures. Our study expands the mutation spectrum of the HL genes and emphasizes the utility of exome sequencing coupled with bioinformatics tools for clinical genetic diagnosis, prognosis, and family counseling.

听力损失（HL）是一种临床和遗传异质性疾病，是人类最常见的感觉缺陷。本研究旨在破译巴基斯坦两个大近亲家庭（GCNF-01、GCNF-03）发生 HL 的遗传原因。两个家族的家族史和纯音听力测试均提示舌前 HL，而 GCNF-01 受影响的个体也存在视力低下和平衡问题，与 I 型亚瑟综合征 (USH1) 的主要特征一致。外显子组测序和分离分析揭示了USH1C的一个新剪接位点变异 (c.877-1G > A) ，该变异与 GCNF01 家族中的 USH1 表型一起出现。虽然 GCNF-03 家族的受影响个体对于 c.716 T > A 是纯合的，但 p.(Val239Asp) 先前报道了SLC26A4的致病性变异。两种变体在控制数据库中的频率都非常低。计算机诱变和 3 维模拟分析表明，这两种变体对蛋白质折叠和二级结构都有有害影响。我们的研究扩大了 HL 基因的突变谱，并强调了外显子组测序与生物信息学工具在临床遗传诊断、预后和家庭咨询中的实用性。