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Abstract：
Hearing loss is a clinically and genetically heterogeneous disorder, with over 148 genes and 170 loci associated with its pathogenesis. The spectrum and frequency of causal variants vary across different genetic ancestries and are more prevalent in populations that practice consanguineous marriages. Pakistan has a rich history of autosomal recessive gene discovery related to non-syndromic hearing loss. Since the first linkage analysis with a Pakistani family that led to the mapping of the DFNB1 locus on chromosome 13, 51 genes associated with this disorder have been identified in this population. Among these, 13 of the most prevalent genes, namely CDH23, CIB2, CLDN14, GJB2, HGF, MARVELD2, MYO7A, MYO15A, MSRB3, OTOF, SLC26A4, TMC1 and TMPRSS3, account for more than half of all cases of profound hearing loss, while the prevalence of other genes is less than 2% individually. In this review, we discuss the most common autosomal recessive non-syndromic hearing loss genes in Pakistani individuals as well as the genetic mapping and sequencing approaches used to discover them. Furthermore, we identified enriched gene ontology terms and common pathways involved in these 51 autosomal recessive non-syndromic hearing loss genes to gain a better understanding of the underlying mechanisms. Establishing a molecular understanding of the disorder may aid in reducing its future prevalence by enabling timely diagnostics and genetic counselling, leading to more effective clinical management and treatments of hearing loss.
摘要：
听力损失是一种临床和遗传异质性疾病，有超过148个基因和170个位点与其发病机制相关。因果变异的频谱和频率在不同的遗传祖先之间有所不同，并且在实行近亲婚姻的人群中更为普遍。巴基斯坦具有与非综合征性听力损失相关的常染色体隐性基因发现的丰富历史。自从与巴基斯坦家族的首次连锁分析导致DFNB1基因座在13号染色体上的定位以来，已在该人群中鉴定出与该疾病相关的51个基因。其中,13个最普遍的基因，即CDH23，CIB2，CLDN14，GJB2，HGF，MARVELD2,MYO7A,MYO15A,MSRB3,OTOF,SLC26A4，TMC1和TMPRSS3占所有严重听力损失病例的一半以上，而其他基因的患病率分别低于2%。在这次审查中,我们讨论了巴基斯坦人最常见的常染色体隐性遗传非综合征性听力损失基因,以及用于发现这些基因的遗传图谱和测序方法.此外，我们确定了这51个常染色体隐性遗传非综合征性听力损失基因中涉及的丰富的基因本体论术语和共同通路,以更好地了解潜在机制.建立对该疾病的分子理解可能有助于通过及时诊断和遗传咨询来降低其未来的患病率。导致更有效的听力损失的临床管理和治疗。
