Recurrent and Novel Pathogenic Variants in Genes Involved with Hearing Loss in the Pakistani Population.

IF 4.1 3区 医学 Q1 GENETICS & HEREDITY
Madiha Shadab, Afif Ben-Mahmoud, Luis Nicolás Martínez Völter, Ansar Ahmed Abbasi, Bonsu Ku, Ahsan Ejaz, Zahid Latif, Vijay Gupta, Daniel Owrang, Mi-Hyeon Jang, Zijin Zhang, Rahema Mohammad, Henry Houlden, Hyung-Goo Kim, Barbara Vona
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引用次数: 0

Abstract

Background: Molecular diagnostic rates for hereditary hearing loss vary by genetic ancestry, highlighting the importance of population-specific studies. In Pakistan, where consanguineous marriages are prevalent, genetic research has identified many autosomal recessive genes, advancing understanding of rare and novel hearing loss mechanisms. This study aimed to identify pathogenic genetic variants in 31 families from Azad Kashmir, Pakistan, presenting non-syndromic hearing loss.

Methods: We conducted exome sequencing and bioinformatics analysis, and targeted gene sequencing on 31 Pakistani families with hearing loss.

Results: We identified ten pathogenic, three likely pathogenic variants, and one variant of uncertain significance, comprising six nonsense, four missense, three frameshift, and one deep intronic variant, across ten hearing loss-associated genes (MYO15A, GJB2, SLC26A4, TMC1, HGF, TMIE, SLC19A2, KCNE1, ILDR, PCDH15 and MYO6) in 25 families. The overall diagnostic rate, including families with pathogenic and likely pathogenic variants, was 77.4%. GJB2 was the most frequently affected gene, identified in seven families. Thirteen out of 14 identified variants were homozygous. Notably, we identified two novel variants: MYO15A (NM_016239.4, DFNB3) c.870C>G, p.(Tyr290*) and MYO6 (NM_016239.4, DFNB37) c.3465del, p.(Pro1156Leufs*9). Additionally, we identified c.10475dupA, p.(Leu3493Alafs*25) in MYO15A (NM_016239.4, DFNB3) and c.617T>A, p.(Leu206*) in SLC26A4 (NM_000441.2, DFNB4), previously documented in ClinVar but unpublished. We also propose SLC19A2 as a candidate gene presenting as non-syndromic hearing loss, despite its association with thiamine-responsive megaloblastic anemia syndrome.

Conclusion: Our work expands the genotypic and phenotypic spectrum of hearing loss by emphasizing the importance of investigating under-represented groups to identify unique genetic variants and clinical characteristics. Such efforts deepen understanding of genetic diversity in under-represented populations to improve diagnosis and treatment strategies.

巴基斯坦人群中听力损失相关基因的复发性和新型致病变异。
背景:遗传性听力损失的分子诊断率因遗传血统而异,这突出了人群特异性研究的重要性。在近亲婚姻盛行的巴基斯坦,遗传学研究发现了许多常染色体隐性基因,促进了对罕见和新型听力损失机制的理解。本研究旨在鉴定来自巴基斯坦Azad Kashmir的31个非综合征性听力损失家庭的致病基因变异。方法:对31个巴基斯坦听力损失家庭进行外显子组测序和生物信息学分析,并进行靶向基因测序。结果:我们在25个家族的10个听力损失相关基因(MYO15A、GJB2、SLC26A4、TMC1、HGF、TMIE、SLC19A2、KCNE1、ILDR、PCDH15和MYO6)中鉴定出10个致病变异、3个可能致病变异和1个不确定意义的变异,包括6个无义、4个错义、3个移码和1个深内含子变异。包括致病和可能致病变异的家庭在内的总诊断率为77.4%。GJB2是最常见的受影响基因,在7个家族中发现。14个被鉴定的变异中有13个是纯合的。值得注意的是,我们发现了两个新的变异:MYO15A (NM_016239.4, DFNB3) c.870C>G, p.(Tyr290*)和MYO6 (NM_016239.4, DFNB37) c.3465del, p.(Pro1156Leufs*9)。此外,我们在MYO15A (NM_016239.4, DFNB3)中发现了c.10475dupA, p.(Leu3493Alafs*25),在SLC26A4 (NM_000441.2, DFNB4)中发现了c.617T>A, p.(Leu206*),之前在ClinVar中有记录,但未发表。尽管SLC19A2与硫胺素反应性巨幼细胞性贫血综合征有关,但我们也提出SLC19A2是一种表现为非综合征性听力损失的候选基因。结论:我们的工作通过强调调查代表性不足的群体以确定独特的遗传变异和临床特征的重要性,扩大了听力损失的基因型和表型谱。这些努力加深了对代表性不足人群遗传多样性的了解,以改进诊断和治疗策略。
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
CiteScore
7.80
自引率
2.50%
发文量
53
审稿时长
>12 weeks
期刊介绍: Molecular Diagnosis & Therapy welcomes current opinion articles on emerging or contentious issues, comprehensive narrative reviews, systematic reviews (as outlined by the PRISMA statement), original research articles (including short communications) and letters to the editor. All manuscripts are subject to peer review by international experts.
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