A novel frameshift variant in the TMPRSS3 gene causes nonsyndromic hearing loss in a consanguineous family.

IF 2.1 4区 医学 Q3 GENETICS & HEREDITY BMC Medical Genomics Pub Date : 2024-11-29 DOI:10.1186/s12920-024-02055-7
Nahid Rezaie, Saeedeh Sadat Ghazanfari, Seyede Mahsa Mousavikia, Nader Mansour Samaei, Morteza Oladnabi, Abdolazim Sarli, Teymoor Khosravi
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Abstract

Background: Hearing Loss (HL) is the most common sensorineural condition in humans. Mutations in the TMPRSS3 gene (DNFB8/10 locus) have been linked to autosomal recessive non-syndromic hearing loss (ARNSHL).

Methods: Whole-exome sequencing (WES) was utilized to identify disease-causing variants in a proband from Iran with ARNSHL who presented clinically with sensorineural, bilateral, and prelingual HL. The pathogenicity and novelty of the identified variant were assessed using various databases. A co-segregation study was also performed to confirm the presence of the variant in the proband's parents. Additionally, the secondary and tertiary structures of the mutant TMPRSS3 protein were predicted using bioinformatics tools. Furthermore, a global mutational spectrum of TMPRSS3 was created and statistically analyzed. The Iranome database was also used to identify other putative mutations in the TMPRSS3 gene in the Iranian population.

Results: We identified a novel homozygous single nucleotide deletion in TMPRSS3 (c.297delA, p.Asp100ThrfsTer52) in the proband. This is the first report of this mutation in a patient with ARNSHL. Sanger sequencing confirmed that this variant co-segregated from the proband's parents. Bioinformatic tools classified this novel variant as likely pathogenic. Additionally, 49.55% of families with TMPRSS3-related HL patients were shown to have consanguinity, consistent with our study. The Iranome database also revealed the c.268G > A variant as a putative novel mutation in TMPRSS3.

Conclusion: This research expanded the pool of evidence regarding the association between mutations in the TMPRSS3 gene and ARNSHL. The finding confirmed that a single nucleotide deletion caused HL in the proband, suggesting that genetic testing, such as WES, is a robust technique for diagnosing patients with this condition.

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一种新的TMPRSS3基因移码变异导致近亲家庭的非综合征性听力损失。
背景:听力损失(HL)是人类最常见的感觉神经疾病。TMPRSS3基因(DNFB8/10位点)突变与常染色体隐性非综合征性听力损失(ARNSHL)有关。方法:利用全外显子组测序(WES)鉴定来自伊朗的ARNSHL先证患者的致病变异,该患者临床表现为感音神经性、双侧和语前HL。利用各种数据库评估鉴定变异的致病性和新颖性。还进行了一项共同分离研究,以确认在先证者的父母中存在该变体。此外,利用生物信息学工具预测了突变体TMPRSS3蛋白的二级和三级结构。建立了TMPRSS3的全球突变谱,并进行了统计分析。伊朗基因组数据库还用于确定伊朗人群中TMPRSS3基因的其他假定突变。结果:我们在先证中发现一个新的TMPRSS3纯合单核苷酸缺失(c.297delA, p.Asp100ThrfsTer52)。这是在ARNSHL患者中首次报道这种突变。桑格测序证实这种变异与先证者的父母共分离。生物信息学工具将这种新变异归类为可能致病。此外,49.55%的tmprss3相关HL患者家庭有血缘关系,与我们的研究一致。Iranome数据库还显示,c.268G > A变异是TMPRSS3的一个假定的新突变。结论:本研究扩大了关于TMPRSS3基因突变与ARNSHL之间关系的证据池。这一发现证实了先证者的单核苷酸缺失导致HL,这表明基因检测,如WES,是诊断HL患者的一种有效技术。
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来源期刊
BMC Medical Genomics
BMC Medical Genomics 医学-遗传学
CiteScore
3.90
自引率
0.00%
发文量
243
审稿时长
3.5 months
期刊介绍: BMC Medical Genomics is an open access journal publishing original peer-reviewed research articles in all aspects of functional genomics, genome structure, genome-scale population genetics, epigenomics, proteomics, systems analysis, and pharmacogenomics in relation to human health and disease.
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