Improved diagnosis of rare disease patients through systematic detection of runs of homozygosity
Autozygosity is associated with an increased risk of genetic rare disease, thus being a relevant factor for clinical genetic studies. More than 2400 exome sequencing data sets were analyzed and screened for autozygosity on the basis of detection of >1 Mbp runs of homozygosity (ROHs). A model was...
| Autores: | , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Estado: | Versión aceptada para publicación |
| Fecha de publicación: | 2020 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/174442 |
| Acceso en línea: | https://hdl.handle.net/2445/174442 |
| Access Level: | acceso abierto |
| Palabra clave: | Malalties hereditàries Endogàmia i exogàmia Consanguinitat Genetic diseases Endogamy and exogamy Consanguinity |
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Improved diagnosis of rare disease patients through systematic detection of runs of homozygosityMatalonga Borrel, LesleyLaurie, StevenPapakonstantinou, AnastasiosPiscia, DavideMereu, ElisabettaBullich, GemmaThompson, RachelHorvath, RitaPérez Jurado, Luis A.Riess, OlafGut, Ivovan Ommen, Gert JanLochmüller, HannsBeltrán, SergiRare Disease-Connect Genome-Phenome Analysis Platform data contributorsUndiagnosed Rare Disease Programme of Catalonia data contibutorsCormand Rifà, BruBalcells Comas, SusanaGrinberg Vaisman, Daniel RaúlUrreizti, RoserGarrabou Tornos, GlòriaMalalties hereditàriesEndogàmia i exogàmiaConsanguinitatGenetic diseasesEndogamy and exogamyConsanguinityAutozygosity is associated with an increased risk of genetic rare disease, thus being a relevant factor for clinical genetic studies. More than 2400 exome sequencing data sets were analyzed and screened for autozygosity on the basis of detection of >1 Mbp runs of homozygosity (ROHs). A model was built to predict if an individual is likely to be a consanguineous offspring (accuracy, 98%), and probability of consanguinity ranges were established according to the total ROH size. Application of the model resulted in the reclassification of the consanguinity status of 12% of the patients. The analysis of a subset of 79 consanguineous cases with the Rare Disease (RD)-Connect Genome-Phenome Analysis Platform, combining variant filtering and homozygosity mapping, enabled a 50% reduction in the number of candidate variants and the identification of homozygous pathogenic variants in 41 patients, with an overall diagnostic yield of 52%. The newly defined consanguinity ranges provide, for the first time, specific ROH thresholds to estimate inbreeding within a pedigree on disparate exome sequencing data, enabling confirmation or (re)classification of consanguineous status, hence increasing the efficiency of molecular diagnosis and reporting on secondary consanguinity findings, as recommended by American College of Medical Genetics and Genomics guidelinesAmerican Society for Investigative Pathology and the Association for Molecular Pathology2020info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/174442Articles publicats en revistes (Genètica, Microbiologia i Estadística)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1016/j.jmoldx.2020.06.008Journal of Molecular Diagnostics, 2020, vol. 22, num. 9, p. 1205-1215https://doi.org/10.1016/j.jmoldx.2020.06.008info:eu-repo/grantAgreement/EC/H2020/779257info:eu-repo/grantAgreement/EC/H2020/825575info:eu-repo/grantAgreement/EC/FP7/305444cc-by-nc-nd (c), Matalonga Borrel et. al., 2020http://creativecommons.org/licenses/by-nc-nd/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1744422026-05-27T06:46:51Z |
| dc.title.none.fl_str_mv |
Improved diagnosis of rare disease patients through systematic detection of runs of homozygosity |
| title |
Improved diagnosis of rare disease patients through systematic detection of runs of homozygosity |
| spellingShingle |
Improved diagnosis of rare disease patients through systematic detection of runs of homozygosity Matalonga Borrel, Lesley Malalties hereditàries Endogàmia i exogàmia Consanguinitat Genetic diseases Endogamy and exogamy Consanguinity |
| title_short |
Improved diagnosis of rare disease patients through systematic detection of runs of homozygosity |
| title_full |
Improved diagnosis of rare disease patients through systematic detection of runs of homozygosity |
| title_fullStr |
Improved diagnosis of rare disease patients through systematic detection of runs of homozygosity |
| title_full_unstemmed |
Improved diagnosis of rare disease patients through systematic detection of runs of homozygosity |
| title_sort |
Improved diagnosis of rare disease patients through systematic detection of runs of homozygosity |
| dc.creator.none.fl_str_mv |
Matalonga Borrel, Lesley Laurie, Steven Papakonstantinou, Anastasios Piscia, Davide Mereu, Elisabetta Bullich, Gemma Thompson, Rachel Horvath, Rita Pérez Jurado, Luis A. Riess, Olaf Gut, Ivo van Ommen, Gert Jan Lochmüller, Hanns Beltrán, Sergi Rare Disease-Connect Genome-Phenome Analysis Platform data contributors Undiagnosed Rare Disease Programme of Catalonia data contibutors Cormand Rifà, Bru Balcells Comas, Susana Grinberg Vaisman, Daniel Raúl Urreizti, Roser Garrabou Tornos, Glòria |
| author |
Matalonga Borrel, Lesley |
| author_facet |
Matalonga Borrel, Lesley Laurie, Steven Papakonstantinou, Anastasios Piscia, Davide Mereu, Elisabetta Bullich, Gemma Thompson, Rachel Horvath, Rita Pérez Jurado, Luis A. Riess, Olaf Gut, Ivo van Ommen, Gert Jan Lochmüller, Hanns Beltrán, Sergi Rare Disease-Connect Genome-Phenome Analysis Platform data contributors Undiagnosed Rare Disease Programme of Catalonia data contibutors Cormand Rifà, Bru Balcells Comas, Susana Grinberg Vaisman, Daniel Raúl Urreizti, Roser Garrabou Tornos, Glòria |
| author_role |
author |
| author2 |
Laurie, Steven Papakonstantinou, Anastasios Piscia, Davide Mereu, Elisabetta Bullich, Gemma Thompson, Rachel Horvath, Rita Pérez Jurado, Luis A. Riess, Olaf Gut, Ivo van Ommen, Gert Jan Lochmüller, Hanns Beltrán, Sergi Rare Disease-Connect Genome-Phenome Analysis Platform data contributors Undiagnosed Rare Disease Programme of Catalonia data contibutors Cormand Rifà, Bru Balcells Comas, Susana Grinberg Vaisman, Daniel Raúl Urreizti, Roser Garrabou Tornos, Glòria |
| author2_role |
author author author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Malalties hereditàries Endogàmia i exogàmia Consanguinitat Genetic diseases Endogamy and exogamy Consanguinity |
| topic |
Malalties hereditàries Endogàmia i exogàmia Consanguinitat Genetic diseases Endogamy and exogamy Consanguinity |
| description |
Autozygosity is associated with an increased risk of genetic rare disease, thus being a relevant factor for clinical genetic studies. More than 2400 exome sequencing data sets were analyzed and screened for autozygosity on the basis of detection of >1 Mbp runs of homozygosity (ROHs). A model was built to predict if an individual is likely to be a consanguineous offspring (accuracy, 98%), and probability of consanguinity ranges were established according to the total ROH size. Application of the model resulted in the reclassification of the consanguinity status of 12% of the patients. The analysis of a subset of 79 consanguineous cases with the Rare Disease (RD)-Connect Genome-Phenome Analysis Platform, combining variant filtering and homozygosity mapping, enabled a 50% reduction in the number of candidate variants and the identification of homozygous pathogenic variants in 41 patients, with an overall diagnostic yield of 52%. The newly defined consanguinity ranges provide, for the first time, specific ROH thresholds to estimate inbreeding within a pedigree on disparate exome sequencing data, enabling confirmation or (re)classification of consanguineous status, hence increasing the efficiency of molecular diagnosis and reporting on secondary consanguinity findings, as recommended by American College of Medical Genetics and Genomics guidelines |
| publishDate |
2020 |
| dc.date.none.fl_str_mv |
2020 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/acceptedVersion info:eu-repo/semantics/publishedVersion |
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article |
| status_str |
acceptedVersion |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/2445/174442 |
| url |
https://hdl.handle.net/2445/174442 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
Reproducció del document publicat a: https://doi.org/10.1016/j.jmoldx.2020.06.008 Journal of Molecular Diagnostics, 2020, vol. 22, num. 9, p. 1205-1215 https://doi.org/10.1016/j.jmoldx.2020.06.008 info:eu-repo/grantAgreement/EC/H2020/779257 info:eu-repo/grantAgreement/EC/H2020/825575 info:eu-repo/grantAgreement/EC/FP7/305444 |
| dc.rights.none.fl_str_mv |
cc-by-nc-nd (c), Matalonga Borrel et. al., 2020 http://creativecommons.org/licenses/by-nc-nd/3.0/es/ info:eu-repo/semantics/openAccess |
| rights_invalid_str_mv |
cc-by-nc-nd (c), Matalonga Borrel et. al., 2020 http://creativecommons.org/licenses/by-nc-nd/3.0/es/ |
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openAccess |
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application/pdf |
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American Society for Investigative Pathology and the Association for Molecular Pathology |
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American Society for Investigative Pathology and the Association for Molecular Pathology |
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Articles publicats en revistes (Genètica, Microbiologia i Estadística) reponame:Dipòsit Digital de la UB instname:Universidad de Barcelona |
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Universidad de Barcelona |
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Dipòsit Digital de la UB |
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Dipòsit Digital de la UB |
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