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Mutation analysis of SLC26A4 (Pendrin) gene in a Brazilian sample of hearing-impaired subjects

BACKGROUND: Mutations in the SLC26A4 gene are associated with Pendred syndrome and autosomal recessive non-syndromic deafness (DFNB4). Both disorders have similar audiologic characteristics: bilateral hearing loss, often severe or profound, which may be associated with abnormalities of the inner ear...

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Autores principales: Nonose, Renata Watanabe, Lezirovitz, Karina, de Mello Auricchio, Maria Teresa Balester, Batissoco, Ana Carla, Yamamoto, Guilherme Lopes, Mingroni-Netto, Regina Célia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5941635/
https://www.ncbi.nlm.nih.gov/pubmed/29739340
http://dx.doi.org/10.1186/s12881-018-0585-x
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author Nonose, Renata Watanabe
Lezirovitz, Karina
de Mello Auricchio, Maria Teresa Balester
Batissoco, Ana Carla
Yamamoto, Guilherme Lopes
Mingroni-Netto, Regina Célia
author_facet Nonose, Renata Watanabe
Lezirovitz, Karina
de Mello Auricchio, Maria Teresa Balester
Batissoco, Ana Carla
Yamamoto, Guilherme Lopes
Mingroni-Netto, Regina Célia
author_sort Nonose, Renata Watanabe
collection PubMed
description BACKGROUND: Mutations in the SLC26A4 gene are associated with Pendred syndrome and autosomal recessive non-syndromic deafness (DFNB4). Both disorders have similar audiologic characteristics: bilateral hearing loss, often severe or profound, which may be associated with abnormalities of the inner ear, such as dilatation of the vestibular aqueduct or Mondini dysplasia. But, in Pendred syndrome (OMIM #274600), with autosomal recessive inheritance, besides congenital sensorineural deafness, goiter or thyroid dysfunctions are frequently present. The aim of this study was to determine whether mutations in SLC26A4 are a frequent cause of hereditary deafness in Brazilian patients. METHODS: Microsatellite haplotypes linked to SLC26A4 were investigated in 68 families presenting autosomal recessive non-syndromic deafness. In the probands of the 16 families presenting segregation consistent with linkage to SLC26A4, Sanger sequencing of the 20 coding exons was performed. In an additional sample of 15 individuals with suspected Pendred syndrome, because of the presence of hypothyroidism or cochleovestibular malformations, the SLC26A4 gene coding region was also sequenced. RESULTS: In two of the 16 families with indication of linkage to SLC26A4, the probands were found to be compound heterozygotes for probably pathogenic different mutations: three novel (c.1003 T > G (p. F335 V), c.1553G > A (p.W518X), c.2235 + 2 T > C (IVS19 + 2 T > C), and one already described, c.84C > A (p.S28R). Two of the 15 individuals with suspected Pendred syndrome because of hypothyreoidism or cochleovestibular malformations were monoallelic for likely pathogenic mutations: a splice mutation (IVS7 + 2 T > C) and the previously described c.1246A > C (p.T416P). Pathogenic copy number variations were excluded in the monoallelic cases and in those with normal results after Sanger sequencing. Additional mutations in the SLC26A4 gene or other definite molecular cause for deafness were not identified in the monoallelic patients, after exome sequencing. CONCLUSIONS: Biallelic pathogenic mutations in SLC26A4 explained ~ 3% of cases selected because of autosomal recessive deafness. Monoallelic mutations were present in ~ 13% of isolated cases of deafness with cochleovestibular malformations or suspected Pendred syndrome. These data reinforce the importance of mutation screening of SLC26A4 in Brazilian subjects and highlight the elevated frequency of monoallelic patients.
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spelling pubmed-59416352018-05-14 Mutation analysis of SLC26A4 (Pendrin) gene in a Brazilian sample of hearing-impaired subjects Nonose, Renata Watanabe Lezirovitz, Karina de Mello Auricchio, Maria Teresa Balester Batissoco, Ana Carla Yamamoto, Guilherme Lopes Mingroni-Netto, Regina Célia BMC Med Genet Research Article BACKGROUND: Mutations in the SLC26A4 gene are associated with Pendred syndrome and autosomal recessive non-syndromic deafness (DFNB4). Both disorders have similar audiologic characteristics: bilateral hearing loss, often severe or profound, which may be associated with abnormalities of the inner ear, such as dilatation of the vestibular aqueduct or Mondini dysplasia. But, in Pendred syndrome (OMIM #274600), with autosomal recessive inheritance, besides congenital sensorineural deafness, goiter or thyroid dysfunctions are frequently present. The aim of this study was to determine whether mutations in SLC26A4 are a frequent cause of hereditary deafness in Brazilian patients. METHODS: Microsatellite haplotypes linked to SLC26A4 were investigated in 68 families presenting autosomal recessive non-syndromic deafness. In the probands of the 16 families presenting segregation consistent with linkage to SLC26A4, Sanger sequencing of the 20 coding exons was performed. In an additional sample of 15 individuals with suspected Pendred syndrome, because of the presence of hypothyroidism or cochleovestibular malformations, the SLC26A4 gene coding region was also sequenced. RESULTS: In two of the 16 families with indication of linkage to SLC26A4, the probands were found to be compound heterozygotes for probably pathogenic different mutations: three novel (c.1003 T > G (p. F335 V), c.1553G > A (p.W518X), c.2235 + 2 T > C (IVS19 + 2 T > C), and one already described, c.84C > A (p.S28R). Two of the 15 individuals with suspected Pendred syndrome because of hypothyreoidism or cochleovestibular malformations were monoallelic for likely pathogenic mutations: a splice mutation (IVS7 + 2 T > C) and the previously described c.1246A > C (p.T416P). Pathogenic copy number variations were excluded in the monoallelic cases and in those with normal results after Sanger sequencing. Additional mutations in the SLC26A4 gene or other definite molecular cause for deafness were not identified in the monoallelic patients, after exome sequencing. CONCLUSIONS: Biallelic pathogenic mutations in SLC26A4 explained ~ 3% of cases selected because of autosomal recessive deafness. Monoallelic mutations were present in ~ 13% of isolated cases of deafness with cochleovestibular malformations or suspected Pendred syndrome. These data reinforce the importance of mutation screening of SLC26A4 in Brazilian subjects and highlight the elevated frequency of monoallelic patients. BioMed Central 2018-05-08 /pmc/articles/PMC5941635/ /pubmed/29739340 http://dx.doi.org/10.1186/s12881-018-0585-x Text en © The Author(s). 2018 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 Research Article
Nonose, Renata Watanabe
Lezirovitz, Karina
de Mello Auricchio, Maria Teresa Balester
Batissoco, Ana Carla
Yamamoto, Guilherme Lopes
Mingroni-Netto, Regina Célia
Mutation analysis of SLC26A4 (Pendrin) gene in a Brazilian sample of hearing-impaired subjects
title Mutation analysis of SLC26A4 (Pendrin) gene in a Brazilian sample of hearing-impaired subjects
title_full Mutation analysis of SLC26A4 (Pendrin) gene in a Brazilian sample of hearing-impaired subjects
title_fullStr Mutation analysis of SLC26A4 (Pendrin) gene in a Brazilian sample of hearing-impaired subjects
title_full_unstemmed Mutation analysis of SLC26A4 (Pendrin) gene in a Brazilian sample of hearing-impaired subjects
title_short Mutation analysis of SLC26A4 (Pendrin) gene in a Brazilian sample of hearing-impaired subjects
title_sort mutation analysis of slc26a4 (pendrin) gene in a brazilian sample of hearing-impaired subjects
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5941635/
https://www.ncbi.nlm.nih.gov/pubmed/29739340
http://dx.doi.org/10.1186/s12881-018-0585-x
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