Reclassification of candidate splicing variants refines clinically conflicting interpretations in SLC26A4-associated hearing loss.

IF 3.7 2区 医学 Q2 GENETICS & HEREDITY
Yue Liang, Shubin Fang, Xiaoqing Cen, Yueying Wang, Anhai Chen, Lusha Huang, Juan Wang, Wenbin Lei, Guanxia Xiong, Kaitian Chen
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引用次数: 0

Abstract

Purpose: Variants in the human SLC26A4 gene are a major cause of hereditary hearing loss. Many splice site variants have been identified, but their pathogenicity is not well understood.

Methods: In accordance with the guidelines from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, we analysed the spectrum of SLC26A4 gene variants. We performed in silico analysis and in vitro splicing assays to evaluate novel or known variants of uncertain significance that may contribute to aberrant alternative splicing.

Results: In a cohort of 178 patients carrying SLC26A4 variants, selected from 202 hearing loss patients with or without inner ear malformations who underwent SLC26A4 gene testing, we identified a total of 50 variants. Among these, 10 intronic variants potentially affecting splicing collectively accounted for 54.8% of the total allele frequency of all identified variant types and were prioritised for messenger RNA (mRNA) splicing analysis. Further investigation demonstrated that four variants led to distinct types of aberrant splicing outcomes. Overall, the clinical significance of seven splice site variants was reclassified, representing at least 4.34% (14/323) of the variants within our cohort.

Conclusion: By using the standard classification of SLC26A4 variants, our results were able to interpret novel or uncertain SLC26A4 gene variants in a pathogenic or benign variant direction. This approach facilitates more refined genetic counselling for patients carrying SLC26A4 gene variants.

候选剪接变体的重新分类改进了slc26a4相关听力损失的临床相互矛盾的解释。
目的:人类SLC26A4基因的变异是遗传性听力损失的主要原因。许多剪接位点变异已被发现,但其致病性尚不清楚。方法:根据美国医学遗传学与基因组学学会和分子病理学协会的指南,对SLC26A4基因变异谱进行分析。我们进行了硅分析和体外剪接试验,以评估可能导致异常选择性剪接的新的或已知的不确定意义的变异。结果:在178名携带SLC26A4变异的患者中,从202名患有或不患有内耳畸形的听力损失患者中选择,进行了SLC26A4基因检测,我们共鉴定出50种变异。其中,10个内含子变异可能影响剪接,占所有已鉴定变异类型总等位基因频率的54.8%,被优先用于信使RNA (mRNA)剪接分析。进一步的研究表明,四种变体导致不同类型的异常剪接结果。总体而言,7个剪接位点变异的临床意义被重新分类,代表了我们队列中至少4.34%(14/323)的变异。结论:通过SLC26A4变异的标准分类,我们的研究结果能够在致病或良性变异方向上解释新的或不确定的SLC26A4基因变异。这种方法有助于对携带SLC26A4基因变异的患者进行更精细的遗传咨询。
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来源期刊
Journal of Medical Genetics
Journal of Medical Genetics 医学-遗传学
CiteScore
7.60
自引率
2.50%
发文量
92
审稿时长
4-8 weeks
期刊介绍: Journal of Medical Genetics is a leading international peer-reviewed journal covering original research in human genetics, including reviews of and opinion on the latest developments. Articles cover the molecular basis of human disease including germline cancer genetics, clinical manifestations of genetic disorders, applications of molecular genetics to medical practice and the systematic evaluation of such applications worldwide.
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