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Novel EYA4 variant in Slovak family with late onset autosomal dominant hearing loss: a case report
BACKGROUND: Progressive bilateral sensorineural deafness in postlingual period may be linked to many different etiologies including genetic factors. Identification of the exact deafness cause may, therefore, be quite challenging. Here we present a family with late-onset hearing loss as an autosomal...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525401/ https://www.ncbi.nlm.nih.gov/pubmed/31101089 http://dx.doi.org/10.1186/s12881-019-0806-y |
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author | Varga, Lukas Danis, Daniel Skopkova, Martina Masindova, Ivica Slobodova, Zuzana Demesova, Lucia Profant, Milan Gasperikova, Daniela |
author_facet | Varga, Lukas Danis, Daniel Skopkova, Martina Masindova, Ivica Slobodova, Zuzana Demesova, Lucia Profant, Milan Gasperikova, Daniela |
author_sort | Varga, Lukas |
collection | PubMed |
description | BACKGROUND: Progressive bilateral sensorineural deafness in postlingual period may be linked to many different etiologies including genetic factors. Identification of the exact deafness cause may, therefore, be quite challenging. Here we present a family with late-onset hearing loss as an autosomal dominant trait caused by a novel EYA4 mutation. CASE PRESENTATION: Forty-four years old female proband clinically investigated for progressive hearing loss and occasional dizziness with positive family history for deafness was subject to molecular-genetic testing. Patient’s DNA sample was analyzed by whole exome sequencing. We identified a novel missense variant c.804G > C located at the last base pair of exon 10 in EYA4. Candidate variant was confirmed by Sanger sequencing in the proband and her family members. In silico prediction tools and co-segregation analysis were used to indicate pathogenicity of the identified variant. To confirm our hypothesis, we performed minigene assay to demonstrate if the transcript of exon 10 in EYA4 is present. We provide evidence that this mutation in vitro compromises donor site functionality and causes exon 10 skipping and frameshift that most likely results in nonsense-mediated mRNA decay. The onset of moderate to severe hearing loss in the family ranged from 10 to 40 years. The normal cardiac phenotype was confirmed by ECG and echocardiography. CONCLUSIONS: We identified a novel EYA4 mutation associated with adult-onset autosomal dominant sensorineural hearing loss. This report extends the knowledge of spectrum of EYA4 mutations and demonstrates the pathogenicity of a variant affecting specific position in the gene. A comprehensive review of known EYA4 mutations is also given and their impact on cardiac phenotype is discussed. Our findings highlight the importance of genetic testing and complex clinical assessment in patients with familial progressive hearing loss. |
format | Online Article Text |
id | pubmed-6525401 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-65254012019-05-24 Novel EYA4 variant in Slovak family with late onset autosomal dominant hearing loss: a case report Varga, Lukas Danis, Daniel Skopkova, Martina Masindova, Ivica Slobodova, Zuzana Demesova, Lucia Profant, Milan Gasperikova, Daniela BMC Med Genet Case Report BACKGROUND: Progressive bilateral sensorineural deafness in postlingual period may be linked to many different etiologies including genetic factors. Identification of the exact deafness cause may, therefore, be quite challenging. Here we present a family with late-onset hearing loss as an autosomal dominant trait caused by a novel EYA4 mutation. CASE PRESENTATION: Forty-four years old female proband clinically investigated for progressive hearing loss and occasional dizziness with positive family history for deafness was subject to molecular-genetic testing. Patient’s DNA sample was analyzed by whole exome sequencing. We identified a novel missense variant c.804G > C located at the last base pair of exon 10 in EYA4. Candidate variant was confirmed by Sanger sequencing in the proband and her family members. In silico prediction tools and co-segregation analysis were used to indicate pathogenicity of the identified variant. To confirm our hypothesis, we performed minigene assay to demonstrate if the transcript of exon 10 in EYA4 is present. We provide evidence that this mutation in vitro compromises donor site functionality and causes exon 10 skipping and frameshift that most likely results in nonsense-mediated mRNA decay. The onset of moderate to severe hearing loss in the family ranged from 10 to 40 years. The normal cardiac phenotype was confirmed by ECG and echocardiography. CONCLUSIONS: We identified a novel EYA4 mutation associated with adult-onset autosomal dominant sensorineural hearing loss. This report extends the knowledge of spectrum of EYA4 mutations and demonstrates the pathogenicity of a variant affecting specific position in the gene. A comprehensive review of known EYA4 mutations is also given and their impact on cardiac phenotype is discussed. Our findings highlight the importance of genetic testing and complex clinical assessment in patients with familial progressive hearing loss. BioMed Central 2019-05-17 /pmc/articles/PMC6525401/ /pubmed/31101089 http://dx.doi.org/10.1186/s12881-019-0806-y Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Case Report Varga, Lukas Danis, Daniel Skopkova, Martina Masindova, Ivica Slobodova, Zuzana Demesova, Lucia Profant, Milan Gasperikova, Daniela Novel EYA4 variant in Slovak family with late onset autosomal dominant hearing loss: a case report |
title | Novel EYA4 variant in Slovak family with late onset autosomal dominant hearing loss: a case report |
title_full | Novel EYA4 variant in Slovak family with late onset autosomal dominant hearing loss: a case report |
title_fullStr | Novel EYA4 variant in Slovak family with late onset autosomal dominant hearing loss: a case report |
title_full_unstemmed | Novel EYA4 variant in Slovak family with late onset autosomal dominant hearing loss: a case report |
title_short | Novel EYA4 variant in Slovak family with late onset autosomal dominant hearing loss: a case report |
title_sort | novel eya4 variant in slovak family with late onset autosomal dominant hearing loss: a case report |
topic | Case Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525401/ https://www.ncbi.nlm.nih.gov/pubmed/31101089 http://dx.doi.org/10.1186/s12881-019-0806-y |
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