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Updated: Oct 7, 2025
Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
Predicting pathogenicity for novel hearing loss mutations based on genetic and protein structure approaches
Paula I Buonfiglio1, Carlos D Bruque2, Vanesa Lotersztein3
1Laboratory of Physiology and Genetics of Hearing. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor Torres", Consejo Nacional de Investigaciones Científicas y Técnicas, INGEBI/CONICET, Vuelta de Obligado 2490- (C1428ADN), Ciudad Autónoma de Buenos Aires, Argentina.
Genetic heterogeneity in severe hearing loss was investigated using whole exome sequencing in Argentinean families. Novel mutations in non-GJB2 genes were identified, highlighting the power of WES and bioinformatics for diagnosing deafness.
Area of Science:
- Genetics
- Audiology
- Bioinformatics
Background:
- Hearing loss is a complex genetic disorder with significant heterogeneity.
- Identifying causative mutations is challenging due to the vast number of genes involved.
- Previous studies often focused on common mutations, leaving many cases undiagnosed.
Purpose of the Study:
- To identify the genetic causes of severe/profound sensorineural hearing loss in Argentinean families.
- To explore the utility of whole exome sequencing (WES) in diagnosing hearing loss.
- To discover novel mutations in deafness-related genes.
Main Methods:
- Whole exome sequencing was performed on 32 unrelated Argentinean families with severe/profound deafness.
- GJB2-GJB6 mutations were excluded prior to WES.
- Novel variants were analyzed using protein modeling and stability analysis.
Main Results:
- Mutations in 16 known deafness genes were identified in 20 patients.
- Eleven novel variants in 9 different non-GJB2 genes were discovered.
- Bioinformatic analyses were used to predict the pathogenicity of these novel variants.
Conclusions:
- Whole exome sequencing is a valuable tool for identifying genetic variants in heterogeneous hearing loss.
- The study identified novel mutations, expanding the known genetic landscape of deafness.
- Bioinformatic strategies are crucial for interpreting the pathogenicity of newly identified variants.
