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Delineation of Homozygous Variants Associated with Prelingual Sensorineural Hearing Loss in Pakistani Families

Hearing loss is a genetically heterogeneous disorder affecting approximately 360 million people worldwide and is among the most common sensorineural disorders. Here, we report a genetic analysis of seven large consanguineous families segregating prelingual sensorineural hearing loss. Whole-exome seq...

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Autores principales: Noman, Muhammad, Ishaq, Rafaqat, Bukhari, Shazia A., Ahmed, Zubair M., Riazuddin, Saima
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947215/
https://www.ncbi.nlm.nih.gov/pubmed/31835641
http://dx.doi.org/10.3390/genes10121031
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author Noman, Muhammad
Ishaq, Rafaqat
Bukhari, Shazia A.
Ahmed, Zubair M.
Riazuddin, Saima
author_facet Noman, Muhammad
Ishaq, Rafaqat
Bukhari, Shazia A.
Ahmed, Zubair M.
Riazuddin, Saima
author_sort Noman, Muhammad
collection PubMed
description Hearing loss is a genetically heterogeneous disorder affecting approximately 360 million people worldwide and is among the most common sensorineural disorders. Here, we report a genetic analysis of seven large consanguineous families segregating prelingual sensorineural hearing loss. Whole-exome sequencing (WES) revealed seven different pathogenic variants segregating with hearing loss in these families, three novel variants (c.1204G>A, c.322G>T, and c.5587C>T) in TMPRSS3, ESRRB, and OTOF, and four previously reported variants (c.208C>T, c.6371G>A, c.226G>A, and c.494C>T) in LRTOMT, MYO15A, KCNE1, and LHFPL5, respectively. All identified variants had very low frequencies in the control databases and were predicted to have pathogenic effects on the encoded proteins. In addition to being familial, we also found intersibship locus heterogeneity in the evaluated families. The known pathogenic c.226C>T variant identified in KCNE1 only segregates with the hearing loss phenotype in a subset of affected members of the family GCNF21. This study further highlights the challenges of identifying disease-causing variants for highly heterogeneous disorders and reports the identification of three novel and four previously reported variants in seven known deafness genes.
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spelling pubmed-69472152020-01-13 Delineation of Homozygous Variants Associated with Prelingual Sensorineural Hearing Loss in Pakistani Families Noman, Muhammad Ishaq, Rafaqat Bukhari, Shazia A. Ahmed, Zubair M. Riazuddin, Saima Genes (Basel) Communication Hearing loss is a genetically heterogeneous disorder affecting approximately 360 million people worldwide and is among the most common sensorineural disorders. Here, we report a genetic analysis of seven large consanguineous families segregating prelingual sensorineural hearing loss. Whole-exome sequencing (WES) revealed seven different pathogenic variants segregating with hearing loss in these families, three novel variants (c.1204G>A, c.322G>T, and c.5587C>T) in TMPRSS3, ESRRB, and OTOF, and four previously reported variants (c.208C>T, c.6371G>A, c.226G>A, and c.494C>T) in LRTOMT, MYO15A, KCNE1, and LHFPL5, respectively. All identified variants had very low frequencies in the control databases and were predicted to have pathogenic effects on the encoded proteins. In addition to being familial, we also found intersibship locus heterogeneity in the evaluated families. The known pathogenic c.226C>T variant identified in KCNE1 only segregates with the hearing loss phenotype in a subset of affected members of the family GCNF21. This study further highlights the challenges of identifying disease-causing variants for highly heterogeneous disorders and reports the identification of three novel and four previously reported variants in seven known deafness genes. MDPI 2019-12-10 /pmc/articles/PMC6947215/ /pubmed/31835641 http://dx.doi.org/10.3390/genes10121031 Text en © 2019 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 Communication
Noman, Muhammad
Ishaq, Rafaqat
Bukhari, Shazia A.
Ahmed, Zubair M.
Riazuddin, Saima
Delineation of Homozygous Variants Associated with Prelingual Sensorineural Hearing Loss in Pakistani Families
title Delineation of Homozygous Variants Associated with Prelingual Sensorineural Hearing Loss in Pakistani Families
title_full Delineation of Homozygous Variants Associated with Prelingual Sensorineural Hearing Loss in Pakistani Families
title_fullStr Delineation of Homozygous Variants Associated with Prelingual Sensorineural Hearing Loss in Pakistani Families
title_full_unstemmed Delineation of Homozygous Variants Associated with Prelingual Sensorineural Hearing Loss in Pakistani Families
title_short Delineation of Homozygous Variants Associated with Prelingual Sensorineural Hearing Loss in Pakistani Families
title_sort delineation of homozygous variants associated with prelingual sensorineural hearing loss in pakistani families
topic Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947215/
https://www.ncbi.nlm.nih.gov/pubmed/31835641
http://dx.doi.org/10.3390/genes10121031
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