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    Identification and computational analysis of rare variants of known hearing loss genes present in five deaf members of a pakistani kindred

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    Author
    Saleem, Irum Badshah
    Masoud, Muhammad Shareef
    Qasim, Muhammad
    Ali, Muhammad
    Ahmed, Zubair M.
    Date
    2021-11-30
    Journal
    Genes
    Publisher
    MDPI AG
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.3390/genes12121940
    Abstract
    Hearing loss (HL) is the most common neurosensory defect in humans that affects the normal communication. Disease is clinically and genetically heterogeneous, rendering challenges for the molecular diagnosis of affected subjects. This study highlights the phenotypic and genetic complexity of inherited HL in a large consanguineous Pakistan kindred. Audiological evaluation of all affected individuals revealed varying degree of mild to profound sensorineural HL. Whole exome (WES) of four family members followed by Sanger sequencing revealed candidate disease-associated variants in five known deafness genes: GJB2 (c.231G>A; p.(Trp77 *)), SLC26A4 (c.1337A>G; p.(Gln446Arg)), CDH23 (c.2789C>T; p.(Pro930Leu)), KCNQ4 (c.1672G>A; p.(Val558Met)) and MPDZ (c.4124T>C; p.(Val1375Ala)). All identified variants replaced evolutionary conserved residues, were either absent or had low frequencies in the control databases. Our in silico and 3-Dimensional (3D) protein topology analyses support the damaging impact of identified variants on the encoded proteins. However, except for the previously established “pathogenic” and “likely pathogenic” categories for the c.231G>A (p.(Trp77 *)) allele of GJB2 and c.1377A>G (p.(Gln446Arg)) of SLC26A4, respectively, all the remaining identified variants were classified as “uncertain significance” based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) variant pathogenicity guidelines. Our study highlights the complexity of genetic traits in consanguineous families, and the need of combining the functional studies even with the comprehensive profiling of multiple family members to improve the genetic diagnosis in complex inbred families. © 2021 by the authors. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).
    Sponsors
    National Institutes of Health
    Keyword
    CDH23
    Digenic
    Genetic heterogeneity
    GJB2
    Hearing loss
    KCNQ4
    MPDZ
    SLC26A4
    Whole exome sequencing
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/17448
    ae974a485f413a2113503eed53cd6c53
    10.3390/genes12121940
    Scopus Count
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