Identification of a novel in-frame deletion in KCNQ4 (DFNA2A) and evidence of multiple phenocopies of unknown origin in a family with ADSNHL
Autosomal dominant sensorineural hearing loss (ADSNHL) is extremely genetically heterogeneous, making it difficult to molecularly diagnose. We identified a multiplex (n=28 affected) family from the genetic isolate of Newfoundland, Canada with variable SNHL and used a targeted sequencing approach bas...
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ftpubmed:oai:pubmedcentral.nih.gov:3778362 2023-05-15T17:22:28+02:00 Identification of a novel in-frame deletion in KCNQ4 (DFNA2A) and evidence of multiple phenocopies of unknown origin in a family with ADSNHL Abdelfatah, Nelly McComiskey, David A Doucette, Lance Griffin, Anne Moore, Susan J Negrijn, Carol Hodgkinson, Kathy A King, Justin J Larijani, Mani Houston, Jim Stanton, Susan G Young, Terry-Lynn 2013-10 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3778362 http://www.ncbi.nlm.nih.gov/pubmed/23443030 https://doi.org/10.1038/ejhg.2013.5 en eng Nature Publishing Group http://www.ncbi.nlm.nih.gov/pmc/articles/PMC http://www.ncbi.nlm.nih.gov/pubmed/23443030 http://dx.doi.org/10.1038/ejhg.2013.5 Copyright © 2013 Macmillan Publishers Limited Article Text 2013 ftpubmed https://doi.org/10.1038/ejhg.2013.5 2014-10-05T00:46:54Z Autosomal dominant sensorineural hearing loss (ADSNHL) is extremely genetically heterogeneous, making it difficult to molecularly diagnose. We identified a multiplex (n=28 affected) family from the genetic isolate of Newfoundland, Canada with variable SNHL and used a targeted sequencing approach based on population-specific alleles in WFS1, TMPRSS3 and PCDH15; recurrent mutations in GJB2 and GJB6; and frequently mutated exons of KCNQ4, COCH and TECTA. We identified a novel, in-frame deletion (c.806_808delCCT: p.S269del) in the voltage-gated potassium channel KCNQ4 (DFNA2), which in silico modeling predicts to disrupt multimerization of KCNQ4 subunits. Surprisingly, 10/23 deaf relatives are non-carriers of p.S269del. Further molecular characterization of the DFNA2 locus in deletion carriers ruled out the possibility of a pathogenic mutation other than p.S269del at the DFNA2A/B locus and linkage analysis showed significant linkage to DFNA2 (maximum LOD=3.3). Further support of genetic heterogeneity in family 2071 was revealed by comparisons of audio profiles between p.S269del carriers and non-carriers suggesting additional and as yet unknown etiologies. We discuss the serious implications that genetic heterogeneity, in this case observed within a single family, has on molecular diagnostics and genetic counseling. Text Newfoundland PubMed Central (PMC) Canada European Journal of Human Genetics 21 10 1112 1119 |
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Article Abdelfatah, Nelly McComiskey, David A Doucette, Lance Griffin, Anne Moore, Susan J Negrijn, Carol Hodgkinson, Kathy A King, Justin J Larijani, Mani Houston, Jim Stanton, Susan G Young, Terry-Lynn Identification of a novel in-frame deletion in KCNQ4 (DFNA2A) and evidence of multiple phenocopies of unknown origin in a family with ADSNHL |
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Autosomal dominant sensorineural hearing loss (ADSNHL) is extremely genetically heterogeneous, making it difficult to molecularly diagnose. We identified a multiplex (n=28 affected) family from the genetic isolate of Newfoundland, Canada with variable SNHL and used a targeted sequencing approach based on population-specific alleles in WFS1, TMPRSS3 and PCDH15; recurrent mutations in GJB2 and GJB6; and frequently mutated exons of KCNQ4, COCH and TECTA. We identified a novel, in-frame deletion (c.806_808delCCT: p.S269del) in the voltage-gated potassium channel KCNQ4 (DFNA2), which in silico modeling predicts to disrupt multimerization of KCNQ4 subunits. Surprisingly, 10/23 deaf relatives are non-carriers of p.S269del. Further molecular characterization of the DFNA2 locus in deletion carriers ruled out the possibility of a pathogenic mutation other than p.S269del at the DFNA2A/B locus and linkage analysis showed significant linkage to DFNA2 (maximum LOD=3.3). Further support of genetic heterogeneity in family 2071 was revealed by comparisons of audio profiles between p.S269del carriers and non-carriers suggesting additional and as yet unknown etiologies. We discuss the serious implications that genetic heterogeneity, in this case observed within a single family, has on molecular diagnostics and genetic counseling. |
format |
Text |
author |
Abdelfatah, Nelly McComiskey, David A Doucette, Lance Griffin, Anne Moore, Susan J Negrijn, Carol Hodgkinson, Kathy A King, Justin J Larijani, Mani Houston, Jim Stanton, Susan G Young, Terry-Lynn |
author_facet |
Abdelfatah, Nelly McComiskey, David A Doucette, Lance Griffin, Anne Moore, Susan J Negrijn, Carol Hodgkinson, Kathy A King, Justin J Larijani, Mani Houston, Jim Stanton, Susan G Young, Terry-Lynn |
author_sort |
Abdelfatah, Nelly |
title |
Identification of a novel in-frame deletion in KCNQ4 (DFNA2A) and evidence of multiple phenocopies of unknown origin in a family with ADSNHL |
title_short |
Identification of a novel in-frame deletion in KCNQ4 (DFNA2A) and evidence of multiple phenocopies of unknown origin in a family with ADSNHL |
title_full |
Identification of a novel in-frame deletion in KCNQ4 (DFNA2A) and evidence of multiple phenocopies of unknown origin in a family with ADSNHL |
title_fullStr |
Identification of a novel in-frame deletion in KCNQ4 (DFNA2A) and evidence of multiple phenocopies of unknown origin in a family with ADSNHL |
title_full_unstemmed |
Identification of a novel in-frame deletion in KCNQ4 (DFNA2A) and evidence of multiple phenocopies of unknown origin in a family with ADSNHL |
title_sort |
identification of a novel in-frame deletion in kcnq4 (dfna2a) and evidence of multiple phenocopies of unknown origin in a family with adsnhl |
publisher |
Nature Publishing Group |
publishDate |
2013 |
url |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3778362 http://www.ncbi.nlm.nih.gov/pubmed/23443030 https://doi.org/10.1038/ejhg.2013.5 |
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Canada |
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Canada |
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Newfoundland |
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Newfoundland |
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC http://www.ncbi.nlm.nih.gov/pubmed/23443030 http://dx.doi.org/10.1038/ejhg.2013.5 |
op_rights |
Copyright © 2013 Macmillan Publishers Limited |
op_doi |
https://doi.org/10.1038/ejhg.2013.5 |
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European Journal of Human Genetics |
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21 |
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10 |
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1112 |
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1119 |
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1766109160425914368 |