Use of Targeted Exome Sequencing for Molecular Diagnosis of Skeletal Disorders

Detalhes bibliográficos
Autor(a) principal: Polla, Daniel L.
Data de Publicação: 2015
Outros Autores: Cardoso, Maria T. O., Silva, Mayara C. B., Cardoso, Isabela C. C., Medina, Cristina T. N., Araujo, Rosenelle, Fernandes, Camila C. [UNESP], Reis, Alessandra M. M., Andrade, Rosangela V. de, Pereira, Rinaldo W., Pogue, Robert
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da UNESP
Texto Completo: http://dx.doi.org/10.1371/journal.pone.0138314
http://hdl.handle.net/11449/160859
Resumo: Genetic disorders of the skeleton comprise a large group of more than 450 clinically distinct and genetically heterogeneous diseases associated with mutations in more than 300 genes. Achieving a definitive diagnosis is complicated due to the genetic heterogeneity of these disorders, their individual rarity and their diverse radiographic presentations. We used targeted exome sequencing and designed a 1.4Mb panel for simultaneous testing of more than 4,800 exons in 309 genes involved in skeletal disorders. DNA from 69 individuals from 66 families with a known or suspected clinical diagnosis of a skeletal disorder was analyzed. Of 36 cases with a specific clinical hypothesis with a known genetic basis, mutations were identified for eight cases (22%). Of 20 cases with a suspected skeletal disorder but without a specific diagnosis, four causative mutations were identified. Also included were 11 cases with a specific skeletal disorder but for which there was at the time no known associated gene. For these cases, one mutation was identified in a known skeletal disease genes, and re-evaluation of the clinical phenotype in this case changed the diagnoses from osteodys-plasia syndrome to Apert syndrome. These results suggest that the NGS panel provides a fast, accurate and cost-effective molecular diagnostic tool for identifying mutations in a highly genetically heterogeneous set of disorders such as genetic skeletal disorders. The data also stress the importance of a thorough clinical evaluation before DNA sequencing. The strategy should be applicable to other groups of disorders in which the molecular basis is largely known.
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spelling Use of Targeted Exome Sequencing for Molecular Diagnosis of Skeletal DisordersGenetic disorders of the skeleton comprise a large group of more than 450 clinically distinct and genetically heterogeneous diseases associated with mutations in more than 300 genes. Achieving a definitive diagnosis is complicated due to the genetic heterogeneity of these disorders, their individual rarity and their diverse radiographic presentations. We used targeted exome sequencing and designed a 1.4Mb panel for simultaneous testing of more than 4,800 exons in 309 genes involved in skeletal disorders. DNA from 69 individuals from 66 families with a known or suspected clinical diagnosis of a skeletal disorder was analyzed. Of 36 cases with a specific clinical hypothesis with a known genetic basis, mutations were identified for eight cases (22%). Of 20 cases with a suspected skeletal disorder but without a specific diagnosis, four causative mutations were identified. Also included were 11 cases with a specific skeletal disorder but for which there was at the time no known associated gene. For these cases, one mutation was identified in a known skeletal disease genes, and re-evaluation of the clinical phenotype in this case changed the diagnoses from osteodys-plasia syndrome to Apert syndrome. These results suggest that the NGS panel provides a fast, accurate and cost-effective molecular diagnostic tool for identifying mutations in a highly genetically heterogeneous set of disorders such as genetic skeletal disorders. The data also stress the importance of a thorough clinical evaluation before DNA sequencing. The strategy should be applicable to other groups of disorders in which the molecular basis is largely known.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundacao de Apoio a Pesquisa do Distrito FederalCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Univ Catolica Brasilia, Programa Posgrad Ciencias Genom & Biotecnol, Brasilia, DF, BrazilNucleo Genet Secretaria Saude Dist Fed, Brasilia, DF, BrazilUniv Catolica Brasilia, Curso Med, Taguatinga, DF, BrazilUniv Estadual Paulista, Fac Ciencias Agr & Vet, Dept Tecnol, Lab Multiusuario Centralizado Sequenciamento DNA, Jaboticabal, SP, BrazilUniv Estadual Paulista, Fac Ciencias Agr & Vet, Dept Tecnol, Lab Multiusuario Centralizado Sequenciamento DNA, Jaboticabal, SP, BrazilCNPq: 564537/2010-1Fundacao de Apoio a Pesquisa do Distrito Federal: 19300 487/2011Public Library ScienceUniv Catolica BrasiliaNucleo Genet Secretaria Saude Dist FedUniversidade Estadual Paulista (Unesp)Polla, Daniel L.Cardoso, Maria T. O.Silva, Mayara C. B.Cardoso, Isabela C. C.Medina, Cristina T. N.Araujo, RosenelleFernandes, Camila C. [UNESP]Reis, Alessandra M. M.Andrade, Rosangela V. dePereira, Rinaldo W.Pogue, Robert2018-11-26T16:17:02Z2018-11-26T16:17:02Z2015-09-18info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article17application/pdfhttp://dx.doi.org/10.1371/journal.pone.0138314Plos One. San Francisco: Public Library Science, v. 10, n. 9, 17 p., 2015.1932-6203http://hdl.handle.net/11449/16085910.1371/journal.pone.0138314WOS:000361790200090WOS000361790200090.pdfWeb of Sciencereponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengPlos One1,164info:eu-repo/semantics/openAccess2024-06-07T15:31:17Zoai:repositorio.unesp.br:11449/160859Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T14:30:09.559934Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false
dc.title.none.fl_str_mv Use of Targeted Exome Sequencing for Molecular Diagnosis of Skeletal Disorders
title Use of Targeted Exome Sequencing for Molecular Diagnosis of Skeletal Disorders
spellingShingle Use of Targeted Exome Sequencing for Molecular Diagnosis of Skeletal Disorders
Polla, Daniel L.
title_short Use of Targeted Exome Sequencing for Molecular Diagnosis of Skeletal Disorders
title_full Use of Targeted Exome Sequencing for Molecular Diagnosis of Skeletal Disorders
title_fullStr Use of Targeted Exome Sequencing for Molecular Diagnosis of Skeletal Disorders
title_full_unstemmed Use of Targeted Exome Sequencing for Molecular Diagnosis of Skeletal Disorders
title_sort Use of Targeted Exome Sequencing for Molecular Diagnosis of Skeletal Disorders
author Polla, Daniel L.
author_facet Polla, Daniel L.
Cardoso, Maria T. O.
Silva, Mayara C. B.
Cardoso, Isabela C. C.
Medina, Cristina T. N.
Araujo, Rosenelle
Fernandes, Camila C. [UNESP]
Reis, Alessandra M. M.
Andrade, Rosangela V. de
Pereira, Rinaldo W.
Pogue, Robert
author_role author
author2 Cardoso, Maria T. O.
Silva, Mayara C. B.
Cardoso, Isabela C. C.
Medina, Cristina T. N.
Araujo, Rosenelle
Fernandes, Camila C. [UNESP]
Reis, Alessandra M. M.
Andrade, Rosangela V. de
Pereira, Rinaldo W.
Pogue, Robert
author2_role author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Univ Catolica Brasilia
Nucleo Genet Secretaria Saude Dist Fed
Universidade Estadual Paulista (Unesp)
dc.contributor.author.fl_str_mv Polla, Daniel L.
Cardoso, Maria T. O.
Silva, Mayara C. B.
Cardoso, Isabela C. C.
Medina, Cristina T. N.
Araujo, Rosenelle
Fernandes, Camila C. [UNESP]
Reis, Alessandra M. M.
Andrade, Rosangela V. de
Pereira, Rinaldo W.
Pogue, Robert
description Genetic disorders of the skeleton comprise a large group of more than 450 clinically distinct and genetically heterogeneous diseases associated with mutations in more than 300 genes. Achieving a definitive diagnosis is complicated due to the genetic heterogeneity of these disorders, their individual rarity and their diverse radiographic presentations. We used targeted exome sequencing and designed a 1.4Mb panel for simultaneous testing of more than 4,800 exons in 309 genes involved in skeletal disorders. DNA from 69 individuals from 66 families with a known or suspected clinical diagnosis of a skeletal disorder was analyzed. Of 36 cases with a specific clinical hypothesis with a known genetic basis, mutations were identified for eight cases (22%). Of 20 cases with a suspected skeletal disorder but without a specific diagnosis, four causative mutations were identified. Also included were 11 cases with a specific skeletal disorder but for which there was at the time no known associated gene. For these cases, one mutation was identified in a known skeletal disease genes, and re-evaluation of the clinical phenotype in this case changed the diagnoses from osteodys-plasia syndrome to Apert syndrome. These results suggest that the NGS panel provides a fast, accurate and cost-effective molecular diagnostic tool for identifying mutations in a highly genetically heterogeneous set of disorders such as genetic skeletal disorders. The data also stress the importance of a thorough clinical evaluation before DNA sequencing. The strategy should be applicable to other groups of disorders in which the molecular basis is largely known.
publishDate 2015
dc.date.none.fl_str_mv 2015-09-18
2018-11-26T16:17:02Z
2018-11-26T16:17:02Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://dx.doi.org/10.1371/journal.pone.0138314
Plos One. San Francisco: Public Library Science, v. 10, n. 9, 17 p., 2015.
1932-6203
http://hdl.handle.net/11449/160859
10.1371/journal.pone.0138314
WOS:000361790200090
WOS000361790200090.pdf
url http://dx.doi.org/10.1371/journal.pone.0138314
http://hdl.handle.net/11449/160859
identifier_str_mv Plos One. San Francisco: Public Library Science, v. 10, n. 9, 17 p., 2015.
1932-6203
10.1371/journal.pone.0138314
WOS:000361790200090
WOS000361790200090.pdf
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Plos One
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dc.publisher.none.fl_str_mv Public Library Science
publisher.none.fl_str_mv Public Library Science
dc.source.none.fl_str_mv Web of Science
reponame:Repositório Institucional da UNESP
instname:Universidade Estadual Paulista (UNESP)
instacron:UNESP
instname_str Universidade Estadual Paulista (UNESP)
instacron_str UNESP
institution UNESP
reponame_str Repositório Institucional da UNESP
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