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Exome sequencing in undiagnosed inherited and sporadic ataxias

Inherited ataxias are clinically and genetically heterogeneous, and a molecular diagnosis is not possible in most patients. Having excluded common sporadic, inherited and metabolic causes, we used an unbiased whole exome sequencing approach in 35 affected individuals, from 22 randomly selected famil...

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Autores principales: Pyle, Angela, Smertenko, Tania, Bargiela, David, Griffin, Helen, Duff, Jennifer, Appleton, Marie, Douroudis, Konstantinos, Pfeffer, Gerald, Santibanez-Koref, Mauro, Eglon, Gail, Yu-Wai-Man, Patrick, Ramesh, Venkateswaran, Horvath, Rita, Chinnery, Patrick F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4306819/
https://www.ncbi.nlm.nih.gov/pubmed/25497598
http://dx.doi.org/10.1093/brain/awu348
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author Pyle, Angela
Smertenko, Tania
Bargiela, David
Griffin, Helen
Duff, Jennifer
Appleton, Marie
Douroudis, Konstantinos
Pfeffer, Gerald
Santibanez-Koref, Mauro
Eglon, Gail
Yu-Wai-Man, Patrick
Ramesh, Venkateswaran
Horvath, Rita
Chinnery, Patrick F.
author_facet Pyle, Angela
Smertenko, Tania
Bargiela, David
Griffin, Helen
Duff, Jennifer
Appleton, Marie
Douroudis, Konstantinos
Pfeffer, Gerald
Santibanez-Koref, Mauro
Eglon, Gail
Yu-Wai-Man, Patrick
Ramesh, Venkateswaran
Horvath, Rita
Chinnery, Patrick F.
author_sort Pyle, Angela
collection PubMed
description Inherited ataxias are clinically and genetically heterogeneous, and a molecular diagnosis is not possible in most patients. Having excluded common sporadic, inherited and metabolic causes, we used an unbiased whole exome sequencing approach in 35 affected individuals, from 22 randomly selected families of white European descent. We defined the likely molecular diagnosis in 14 of 22 families (64%). This revealed de novo dominant mutations, validated disease genes previously described in isolated families, and broadened the clinical phenotype of known disease genes. The diagnostic yield was the same in both young and older-onset patients, including sporadic cases. We have demonstrated the impact of exome sequencing in a group of patients notoriously difficult to diagnose genetically. This has important implications for genetic counselling and diagnostic service provision.
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spelling pubmed-43068192015-02-24 Exome sequencing in undiagnosed inherited and sporadic ataxias Pyle, Angela Smertenko, Tania Bargiela, David Griffin, Helen Duff, Jennifer Appleton, Marie Douroudis, Konstantinos Pfeffer, Gerald Santibanez-Koref, Mauro Eglon, Gail Yu-Wai-Man, Patrick Ramesh, Venkateswaran Horvath, Rita Chinnery, Patrick F. Brain Reports Inherited ataxias are clinically and genetically heterogeneous, and a molecular diagnosis is not possible in most patients. Having excluded common sporadic, inherited and metabolic causes, we used an unbiased whole exome sequencing approach in 35 affected individuals, from 22 randomly selected families of white European descent. We defined the likely molecular diagnosis in 14 of 22 families (64%). This revealed de novo dominant mutations, validated disease genes previously described in isolated families, and broadened the clinical phenotype of known disease genes. The diagnostic yield was the same in both young and older-onset patients, including sporadic cases. We have demonstrated the impact of exome sequencing in a group of patients notoriously difficult to diagnose genetically. This has important implications for genetic counselling and diagnostic service provision. Oxford University Press 2015-02 2014-12-13 /pmc/articles/PMC4306819/ /pubmed/25497598 http://dx.doi.org/10.1093/brain/awu348 Text en © The Author (2014). 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 Reports
Pyle, Angela
Smertenko, Tania
Bargiela, David
Griffin, Helen
Duff, Jennifer
Appleton, Marie
Douroudis, Konstantinos
Pfeffer, Gerald
Santibanez-Koref, Mauro
Eglon, Gail
Yu-Wai-Man, Patrick
Ramesh, Venkateswaran
Horvath, Rita
Chinnery, Patrick F.
Exome sequencing in undiagnosed inherited and sporadic ataxias
title Exome sequencing in undiagnosed inherited and sporadic ataxias
title_full Exome sequencing in undiagnosed inherited and sporadic ataxias
title_fullStr Exome sequencing in undiagnosed inherited and sporadic ataxias
title_full_unstemmed Exome sequencing in undiagnosed inherited and sporadic ataxias
title_short Exome sequencing in undiagnosed inherited and sporadic ataxias
title_sort exome sequencing in undiagnosed inherited and sporadic ataxias
topic Reports
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4306819/
https://www.ncbi.nlm.nih.gov/pubmed/25497598
http://dx.doi.org/10.1093/brain/awu348
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