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Bi-Allelic Novel Variants in CLIC5 Identified in a Cameroonian Multiplex Family with Non-Syndromic Hearing Impairment

DNA samples from five members of a multiplex non-consanguineous Cameroonian family, segregating prelingual and progressive autosomal recessive non-syndromic sensorineural hearing impairment, underwent whole exome sequencing. We identified novel bi-allelic compound heterozygous pathogenic variants in...

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Autores principales: Wonkam-Tingang, Edmond, Schrauwen, Isabelle, Esoh, Kevin K., Bharadwaj, Thashi, Nouel-Saied, Liz M., Acharya, Anushree, Nasir, Abdul, Adadey, Samuel M., Mowla, Shaheen, Leal, Suzanne M., Wonkam, Ambroise
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690789/
https://www.ncbi.nlm.nih.gov/pubmed/33114113
http://dx.doi.org/10.3390/genes11111249
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author Wonkam-Tingang, Edmond
Schrauwen, Isabelle
Esoh, Kevin K.
Bharadwaj, Thashi
Nouel-Saied, Liz M.
Acharya, Anushree
Nasir, Abdul
Adadey, Samuel M.
Mowla, Shaheen
Leal, Suzanne M.
Wonkam, Ambroise
author_facet Wonkam-Tingang, Edmond
Schrauwen, Isabelle
Esoh, Kevin K.
Bharadwaj, Thashi
Nouel-Saied, Liz M.
Acharya, Anushree
Nasir, Abdul
Adadey, Samuel M.
Mowla, Shaheen
Leal, Suzanne M.
Wonkam, Ambroise
author_sort Wonkam-Tingang, Edmond
collection PubMed
description DNA samples from five members of a multiplex non-consanguineous Cameroonian family, segregating prelingual and progressive autosomal recessive non-syndromic sensorineural hearing impairment, underwent whole exome sequencing. We identified novel bi-allelic compound heterozygous pathogenic variants in CLIC5. The variants identified, i.e., the missense [NM_016929.5:c.224T>C; p.(L75P)] and the splicing (NM_016929.5:c.63+1G>A), were validated using Sanger sequencing in all seven available family members and co-segregated with hearing impairment (HI) in the three hearing impaired family members. The three affected individuals were compound heterozygous for both variants, and all unaffected individuals were heterozygous for one of the two variants. Both variants were absent from the genome aggregation database (gnomAD), the Single Nucleotide Polymorphism Database (dbSNP), and the UK10K and Greater Middle East (GME) databases, as well as from 122 apparently healthy controls from Cameroon. We also did not identify these pathogenic variants in 118 unrelated sporadic cases of non-syndromic hearing impairment (NSHI) from Cameroon. In silico analysis showed that the missense variant CLIC5-p.(L75P) substitutes a highly conserved amino acid residue (leucine), and is expected to alter the stability, the structure, and the function of the CLIC5 protein, while the splicing variant CLIC5-(c.63+1G>A) is predicted to disrupt a consensus donor splice site and alter the splicing of the pre-mRNA. This study is the second report, worldwide, to describe CLIC5 involvement in human hearing impairment, and thus confirms CLIC5 as a novel non-syndromic hearing impairment gene that should be included in targeted diagnostic gene panels.
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spelling pubmed-76907892020-11-27 Bi-Allelic Novel Variants in CLIC5 Identified in a Cameroonian Multiplex Family with Non-Syndromic Hearing Impairment Wonkam-Tingang, Edmond Schrauwen, Isabelle Esoh, Kevin K. Bharadwaj, Thashi Nouel-Saied, Liz M. Acharya, Anushree Nasir, Abdul Adadey, Samuel M. Mowla, Shaheen Leal, Suzanne M. Wonkam, Ambroise Genes (Basel) Article DNA samples from five members of a multiplex non-consanguineous Cameroonian family, segregating prelingual and progressive autosomal recessive non-syndromic sensorineural hearing impairment, underwent whole exome sequencing. We identified novel bi-allelic compound heterozygous pathogenic variants in CLIC5. The variants identified, i.e., the missense [NM_016929.5:c.224T>C; p.(L75P)] and the splicing (NM_016929.5:c.63+1G>A), were validated using Sanger sequencing in all seven available family members and co-segregated with hearing impairment (HI) in the three hearing impaired family members. The three affected individuals were compound heterozygous for both variants, and all unaffected individuals were heterozygous for one of the two variants. Both variants were absent from the genome aggregation database (gnomAD), the Single Nucleotide Polymorphism Database (dbSNP), and the UK10K and Greater Middle East (GME) databases, as well as from 122 apparently healthy controls from Cameroon. We also did not identify these pathogenic variants in 118 unrelated sporadic cases of non-syndromic hearing impairment (NSHI) from Cameroon. In silico analysis showed that the missense variant CLIC5-p.(L75P) substitutes a highly conserved amino acid residue (leucine), and is expected to alter the stability, the structure, and the function of the CLIC5 protein, while the splicing variant CLIC5-(c.63+1G>A) is predicted to disrupt a consensus donor splice site and alter the splicing of the pre-mRNA. This study is the second report, worldwide, to describe CLIC5 involvement in human hearing impairment, and thus confirms CLIC5 as a novel non-syndromic hearing impairment gene that should be included in targeted diagnostic gene panels. MDPI 2020-10-23 /pmc/articles/PMC7690789/ /pubmed/33114113 http://dx.doi.org/10.3390/genes11111249 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wonkam-Tingang, Edmond
Schrauwen, Isabelle
Esoh, Kevin K.
Bharadwaj, Thashi
Nouel-Saied, Liz M.
Acharya, Anushree
Nasir, Abdul
Adadey, Samuel M.
Mowla, Shaheen
Leal, Suzanne M.
Wonkam, Ambroise
Bi-Allelic Novel Variants in CLIC5 Identified in a Cameroonian Multiplex Family with Non-Syndromic Hearing Impairment
title Bi-Allelic Novel Variants in CLIC5 Identified in a Cameroonian Multiplex Family with Non-Syndromic Hearing Impairment
title_full Bi-Allelic Novel Variants in CLIC5 Identified in a Cameroonian Multiplex Family with Non-Syndromic Hearing Impairment
title_fullStr Bi-Allelic Novel Variants in CLIC5 Identified in a Cameroonian Multiplex Family with Non-Syndromic Hearing Impairment
title_full_unstemmed Bi-Allelic Novel Variants in CLIC5 Identified in a Cameroonian Multiplex Family with Non-Syndromic Hearing Impairment
title_short Bi-Allelic Novel Variants in CLIC5 Identified in a Cameroonian Multiplex Family with Non-Syndromic Hearing Impairment
title_sort bi-allelic novel variants in clic5 identified in a cameroonian multiplex family with non-syndromic hearing impairment
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690789/
https://www.ncbi.nlm.nih.gov/pubmed/33114113
http://dx.doi.org/10.3390/genes11111249
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