Exome Sequencing Identifies Novel Variants Causing Hearing Loss in Three Consanguineous Pakistani Families: Insights From Genomics and Bioinformatics Analyses

IF 1.5 4区生物学 Q4 GENETICS & HEREDITY

Annals of Human Genetics Pub Date : 2026-10-07 Epub Date: 2026-09-21 DOI:10.1111/ahg.70061

Zafar Ali, Najeeb Ullah, Muneeba Bibi, Sania Fawad, Sana Khan, Mansoor Ali, Irum Hassan, Sana Fazal, Fazal Akbar, Shahid Baig, Niklas Dahl

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引用次数: 0

Abstract

Background

Hearing impairment is a genetically heterogeneous disorder and represents a significant health concern, particularly in consanguineous populations where autosomal recessive forms are more prevalent. Pakistani families provide an important population for investigating the genetic basis of hereditary hearing impairment.

Objective

The current study was aimed to elucidate the genetic basis of hearing impairment in consanguineous Pakistani families.

Material and Methods

Three consanguineous Pakistani families comprising 11 affected individuals presenting bilateral profound hearing loss were investigated using Exome Sequencing (ES). Sanger sequencing was used for segregation analysis of candidate variant(s) in each pedigree. Structural modeling of both wild-type and mutant proteins were performed using bioinformatic tools to assess the functional impact of candidate variants.

Results

ES data analysis revealed homozygous missense variants in MSRB3 (c.244T>G; p.Cys82Gly), ESRP1 (c.353T>C; p.Leu118Pro) and TMC1 (c.1749C>G; p.Asn583Lys) in family 1, 2, and 3 respectively. These variants are predicted to be “deleterious” by multiple bioinformatic tools, affecting highly conserved residues of candidate protein, and are absent in homozygous form in public databases. Sanger sequencing validated the co-segregation of the candidate variants within their respective families. Structural modeling of the wild-type and mutant proteins predicted that the candidate variants lead to structural alterations that strengthens the evidence supporting their pathogenicity.

Conclusion

This study expands the mutational spectrum of MSRB3, ESRP1 and TMC1 genes associated with hearing loss. Furthermore, carrier screening and genetic counselling can be developed for affected families based on the findings obtained from the current study. The data obtained may also enhance our understanding of the pathophysiology of hearing loss ultimately guiding us in the development of potential therapeutics.

查看原文本刊更多论文

外显子组测序鉴定了导致三个巴基斯坦近亲家庭听力损失的新变异：来自基因组学和生物信息学分析的见解。

背景：听力障碍是一种遗传异质性疾病，是一个重要的健康问题，特别是在常染色体隐性形式更为普遍的近亲人群中。巴基斯坦家庭为研究遗传性听力障碍的遗传基础提供了重要的人群。目的：本研究旨在阐明巴基斯坦近亲家庭中听力障碍的遗传基础。材料和方法：使用外显子组测序（ES）对3个近亲巴基斯坦家庭11名双侧重度听力损失患者进行调查。采用Sanger测序对每个家系的候选变异进行分离分析。使用生物信息学工具对野生型和突变型蛋白进行结构建模，以评估候选变体的功能影响。结果：ES数据分析显示，在家族1、2、3中分别存在MSRB3 （C . 244t >G; p.Cys82Gly）、ESRP1 （C . 353t >C; p.Leu118Pro）和TMC1 （C . 1749c >G; p.Asn583Lys）纯合错义变异。多种生物信息学工具预测这些变异是“有害的”，影响候选蛋白的高度保守残基，并且在公共数据库中不存在纯合形式。Sanger测序验证了候选变异在各自家族中的共分离。野生型和突变蛋白的结构建模预测，候选变异体导致结构改变，这加强了支持其致病性的证据。结论：本研究扩大了与听力损失相关的MSRB3、ESRP1和TMC1基因的突变谱。此外，根据目前的研究结果，可以为受影响的家庭开发携带者筛查和遗传咨询。获得的数据也可以增强我们对听力损失病理生理学的理解，最终指导我们开发潜在的治疗方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Annals of Human Genetics 生物-遗传学

CiteScore

4.20

自引率

0.00%

发文量

审稿时长

3 months

期刊介绍： Annals of Human Genetics publishes material directly concerned with human genetics or the application of scientific principles and techniques to any aspect of human inheritance. Papers that describe work on other species that may be relevant to human genetics will also be considered. Mathematical models should include examples of application to data where possible. Authors are welcome to submit Supporting Information, such as data sets or additional figures or tables, that will not be published in the print edition of the journal, but which will be viewable via the online edition and stored on the website.