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A comprehensive analysis of rare genetic variation in amyotrophic lateral sclerosis in the UK

Amyotrophic lateral sclerosis is a progressive neurodegenerative disease of motor neurons. About 25 genes have been verified as relevant to the disease process, with rare and common variation implicated. We used next generation sequencing and repeat sizing to comprehensively assay genetic variation...

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Autores principales: Morgan, Sarah, Shatunov, Aleksey, Sproviero, William, Jones, Ashley R., Shoai, Maryam, Hughes, Deborah, Al Khleifat, Ahmad, Malaspina, Andrea, Morrison, Karen E., Shaw, Pamela J., Shaw, Christopher E., Sidle, Katie, Orrell, Richard W., Fratta, Pietro, Hardy, John, Pittman, Alan, Al-Chalabi, Ammar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5445258/
https://www.ncbi.nlm.nih.gov/pubmed/28430856
http://dx.doi.org/10.1093/brain/awx082
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author Morgan, Sarah
Shatunov, Aleksey
Sproviero, William
Jones, Ashley R.
Shoai, Maryam
Hughes, Deborah
Al Khleifat, Ahmad
Malaspina, Andrea
Morrison, Karen E.
Shaw, Pamela J.
Shaw, Christopher E.
Sidle, Katie
Orrell, Richard W.
Fratta, Pietro
Hardy, John
Pittman, Alan
Al-Chalabi, Ammar
author_facet Morgan, Sarah
Shatunov, Aleksey
Sproviero, William
Jones, Ashley R.
Shoai, Maryam
Hughes, Deborah
Al Khleifat, Ahmad
Malaspina, Andrea
Morrison, Karen E.
Shaw, Pamela J.
Shaw, Christopher E.
Sidle, Katie
Orrell, Richard W.
Fratta, Pietro
Hardy, John
Pittman, Alan
Al-Chalabi, Ammar
author_sort Morgan, Sarah
collection PubMed
description Amyotrophic lateral sclerosis is a progressive neurodegenerative disease of motor neurons. About 25 genes have been verified as relevant to the disease process, with rare and common variation implicated. We used next generation sequencing and repeat sizing to comprehensively assay genetic variation in a panel of known amyotrophic lateral sclerosis genes in 1126 patient samples and 613 controls. About 10% of patients were predicted to carry a pathological expansion of the C9orf72 gene. We found an increased burden of rare variants in patients within the untranslated regions of known disease-causing genes, driven by SOD1, TARDBP, FUS, VCP, OPTN and UBQLN2. We found 11 patients (1%) carried more than one pathogenic variant (P = 0.001) consistent with an oligogenic basis of amyotrophic lateral sclerosis. These findings show that the genetic architecture of amyotrophic lateral sclerosis is complex and that variation in the regulatory regions of associated genes may be important in disease pathogenesis.
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spelling pubmed-54452582017-05-31 A comprehensive analysis of rare genetic variation in amyotrophic lateral sclerosis in the UK Morgan, Sarah Shatunov, Aleksey Sproviero, William Jones, Ashley R. Shoai, Maryam Hughes, Deborah Al Khleifat, Ahmad Malaspina, Andrea Morrison, Karen E. Shaw, Pamela J. Shaw, Christopher E. Sidle, Katie Orrell, Richard W. Fratta, Pietro Hardy, John Pittman, Alan Al-Chalabi, Ammar Brain Original Articles Amyotrophic lateral sclerosis is a progressive neurodegenerative disease of motor neurons. About 25 genes have been verified as relevant to the disease process, with rare and common variation implicated. We used next generation sequencing and repeat sizing to comprehensively assay genetic variation in a panel of known amyotrophic lateral sclerosis genes in 1126 patient samples and 613 controls. About 10% of patients were predicted to carry a pathological expansion of the C9orf72 gene. We found an increased burden of rare variants in patients within the untranslated regions of known disease-causing genes, driven by SOD1, TARDBP, FUS, VCP, OPTN and UBQLN2. We found 11 patients (1%) carried more than one pathogenic variant (P = 0.001) consistent with an oligogenic basis of amyotrophic lateral sclerosis. These findings show that the genetic architecture of amyotrophic lateral sclerosis is complex and that variation in the regulatory regions of associated genes may be important in disease pathogenesis. Oxford University Press 2017-06 2017-04-18 /pmc/articles/PMC5445258/ /pubmed/28430856 http://dx.doi.org/10.1093/brain/awx082 Text en © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Morgan, Sarah
Shatunov, Aleksey
Sproviero, William
Jones, Ashley R.
Shoai, Maryam
Hughes, Deborah
Al Khleifat, Ahmad
Malaspina, Andrea
Morrison, Karen E.
Shaw, Pamela J.
Shaw, Christopher E.
Sidle, Katie
Orrell, Richard W.
Fratta, Pietro
Hardy, John
Pittman, Alan
Al-Chalabi, Ammar
A comprehensive analysis of rare genetic variation in amyotrophic lateral sclerosis in the UK
title A comprehensive analysis of rare genetic variation in amyotrophic lateral sclerosis in the UK
title_full A comprehensive analysis of rare genetic variation in amyotrophic lateral sclerosis in the UK
title_fullStr A comprehensive analysis of rare genetic variation in amyotrophic lateral sclerosis in the UK
title_full_unstemmed A comprehensive analysis of rare genetic variation in amyotrophic lateral sclerosis in the UK
title_short A comprehensive analysis of rare genetic variation in amyotrophic lateral sclerosis in the UK
title_sort comprehensive analysis of rare genetic variation in amyotrophic lateral sclerosis in the uk
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5445258/
https://www.ncbi.nlm.nih.gov/pubmed/28430856
http://dx.doi.org/10.1093/brain/awx082
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