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Comprehensive Exonic Sequencing of Hemiplegic Migraine-Related Genes in a Cohort of Suspected Probands Identifies Known and Potential Pathogenic Variants

Hemiplegic migraine (HM) is a rare migraine disorder with aura subtype including temporary weakness and visual, sensory, and/or speech symptoms. To date, three main genes—CACNA1A, ATP1A2, and SCN1A—have been found to cause HM. These encode ion channels or transporters, important for regulating neuro...

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Autores principales: Sutherland, Heidi G., Maksemous, Neven, Albury, Cassie L., Ibrahim, Omar, Smith, Robert A., Lea, Rod A., Haupt, Larisa M., Jenkins, Bronwyn, Tsang, Benjamin, Griffiths, Lyn R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693486/
https://www.ncbi.nlm.nih.gov/pubmed/33126486
http://dx.doi.org/10.3390/cells9112368
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author Sutherland, Heidi G.
Maksemous, Neven
Albury, Cassie L.
Ibrahim, Omar
Smith, Robert A.
Lea, Rod A.
Haupt, Larisa M.
Jenkins, Bronwyn
Tsang, Benjamin
Griffiths, Lyn R.
author_facet Sutherland, Heidi G.
Maksemous, Neven
Albury, Cassie L.
Ibrahim, Omar
Smith, Robert A.
Lea, Rod A.
Haupt, Larisa M.
Jenkins, Bronwyn
Tsang, Benjamin
Griffiths, Lyn R.
author_sort Sutherland, Heidi G.
collection PubMed
description Hemiplegic migraine (HM) is a rare migraine disorder with aura subtype including temporary weakness and visual, sensory, and/or speech symptoms. To date, three main genes—CACNA1A, ATP1A2, and SCN1A—have been found to cause HM. These encode ion channels or transporters, important for regulating neuronal ion balance and synaptic transmission, leading to HM being described as a channelopathy. However, <20% of HM cases referred for genetic testing have mutations in these genes and other genes with roles in ion and solute transport, and neurotransmission has also been implicated in some HM cases. In this study, we performed whole exome sequencing for 187 suspected HM probands referred for genetic testing, but found to be negative for CACNA1A, ATP1A2, and SCN1A mutations, and applied targeted analysis of whole exome sequencing data for rare missense or potential protein-altering variants in the PRRT2, PNKD, SLC1A3, SLC2A1, SLC4A4, ATP1A3, and ATP1A4 genes. We identified known mutations and some potentially pathogenic variants in each of these genes in specific cases, suggesting that their screening improves molecular diagnosis for the disorder. However, the majority of HM patients were found not to have candidate mutations in any of the previously reported HM genes, suggesting that additional genetic factors contributing to the disorder are yet to be identified.
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spelling pubmed-76934862020-11-28 Comprehensive Exonic Sequencing of Hemiplegic Migraine-Related Genes in a Cohort of Suspected Probands Identifies Known and Potential Pathogenic Variants Sutherland, Heidi G. Maksemous, Neven Albury, Cassie L. Ibrahim, Omar Smith, Robert A. Lea, Rod A. Haupt, Larisa M. Jenkins, Bronwyn Tsang, Benjamin Griffiths, Lyn R. Cells Article Hemiplegic migraine (HM) is a rare migraine disorder with aura subtype including temporary weakness and visual, sensory, and/or speech symptoms. To date, three main genes—CACNA1A, ATP1A2, and SCN1A—have been found to cause HM. These encode ion channels or transporters, important for regulating neuronal ion balance and synaptic transmission, leading to HM being described as a channelopathy. However, <20% of HM cases referred for genetic testing have mutations in these genes and other genes with roles in ion and solute transport, and neurotransmission has also been implicated in some HM cases. In this study, we performed whole exome sequencing for 187 suspected HM probands referred for genetic testing, but found to be negative for CACNA1A, ATP1A2, and SCN1A mutations, and applied targeted analysis of whole exome sequencing data for rare missense or potential protein-altering variants in the PRRT2, PNKD, SLC1A3, SLC2A1, SLC4A4, ATP1A3, and ATP1A4 genes. We identified known mutations and some potentially pathogenic variants in each of these genes in specific cases, suggesting that their screening improves molecular diagnosis for the disorder. However, the majority of HM patients were found not to have candidate mutations in any of the previously reported HM genes, suggesting that additional genetic factors contributing to the disorder are yet to be identified. MDPI 2020-10-28 /pmc/articles/PMC7693486/ /pubmed/33126486 http://dx.doi.org/10.3390/cells9112368 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
Sutherland, Heidi G.
Maksemous, Neven
Albury, Cassie L.
Ibrahim, Omar
Smith, Robert A.
Lea, Rod A.
Haupt, Larisa M.
Jenkins, Bronwyn
Tsang, Benjamin
Griffiths, Lyn R.
Comprehensive Exonic Sequencing of Hemiplegic Migraine-Related Genes in a Cohort of Suspected Probands Identifies Known and Potential Pathogenic Variants
title Comprehensive Exonic Sequencing of Hemiplegic Migraine-Related Genes in a Cohort of Suspected Probands Identifies Known and Potential Pathogenic Variants
title_full Comprehensive Exonic Sequencing of Hemiplegic Migraine-Related Genes in a Cohort of Suspected Probands Identifies Known and Potential Pathogenic Variants
title_fullStr Comprehensive Exonic Sequencing of Hemiplegic Migraine-Related Genes in a Cohort of Suspected Probands Identifies Known and Potential Pathogenic Variants
title_full_unstemmed Comprehensive Exonic Sequencing of Hemiplegic Migraine-Related Genes in a Cohort of Suspected Probands Identifies Known and Potential Pathogenic Variants
title_short Comprehensive Exonic Sequencing of Hemiplegic Migraine-Related Genes in a Cohort of Suspected Probands Identifies Known and Potential Pathogenic Variants
title_sort comprehensive exonic sequencing of hemiplegic migraine-related genes in a cohort of suspected probands identifies known and potential pathogenic variants
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693486/
https://www.ncbi.nlm.nih.gov/pubmed/33126486
http://dx.doi.org/10.3390/cells9112368
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