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dc.contributor.authorSaleem, Irum Badshah
dc.contributor.authorMasoud, Muhammad Shareef
dc.contributor.authorQasim, Muhammad
dc.contributor.authorAli, Muhammad
dc.contributor.authorAhmed, Zubair M.
dc.date.accessioned2021-12-17T15:22:20Z
dc.date.available2021-12-17T15:22:20Z
dc.date.issued2021-11-30
dc.identifier.urihttp://hdl.handle.net/10713/17448
dc.description.abstractHearing 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/).en_US
dc.description.sponsorshipNational Institutes of Healthen_US
dc.description.urihttps://doi.org/10.3390/genes12121940en_US
dc.language.isoenen_US
dc.publisherMDPI AGen_US
dc.relation.ispartofGenesen_US
dc.subjectCDH23en_US
dc.subjectDigenicen_US
dc.subjectGenetic heterogeneityen_US
dc.subjectGJB2en_US
dc.subjectHearing lossen_US
dc.subjectKCNQ4en_US
dc.subjectMPDZen_US
dc.subjectSLC26A4en_US
dc.subjectWhole exome sequencingen_US
dc.titleIdentification and computational analysis of rare variants of known hearing loss genes present in five deaf members of a pakistani kindreden_US
dc.typeArticleen_US
dc.identifier.doi10.3390/genes12121940
dc.source.volume12
dc.source.issue12


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