Improved Diagnosis of Rare Disease Patients through Systematic Detection of Runs of Homozygosity

Matalonga, Leslie; Laurie, Steven; Papakonstantinou, Anastasios; Piscia, Davide; Mereu, Elisabetta; Bullich, Gemma; Thompson, Rachel; Horvath, Rita; Pérez-Jurado, Luis Alberto; Riess, Olaf; Gut, Ivo; van Ommen, Gert-Jan; Lochmüller, Hanns; Beltran, Sergi; RD–Connect Genome-Phenome Analysis Platform; URD-Cat Data Contributors; Posada De la Paz, Manuel

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...

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Autores:	Matalonga, Leslie, Laurie, Steven, Papakonstantinou, Anastasios, Piscia, Davide, Mereu, Elisabetta, Bullich, Gemma, Thompson, Rachel, Horvath, Rita, Pérez-Jurado, Luis Alberto, Riess, Olaf, Gut, Ivo, van Ommen, Gert-Jan, Lochmüller, Hanns, Beltran, Sergi, RD–Connect Genome-Phenome Analysis Platform, URD-Cat Data Contributors, Posada De la Paz, Manuel
Formato:	artículo
Fecha de publicación:	2020
País:	España
Recursos:	Instituto de Salud Carlos III (ISCIII)
Repositorio:	Repisalud
Idioma:	inglés
OAI Identifier:	oai:repisalud.isciii.es:20.500.12105/15568
Acesso em linha:	http://hdl.handle.net/20.500.12105/15568
Access Level:	acceso abierto
Palavra-chave:	Homozygote Consanguinity Exome Genome, Human Humans Models, Genetic Molecular Diagnostic Techniques Pedigree Polymorphism, Single Nucleotide Rare Diseases Exome Sequencing

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spelling	Improved Diagnosis of Rare Disease Patients through Systematic Detection of Runs of HomozygosityMatalonga, LeslieLaurie, StevenPapakonstantinou, AnastasiosPiscia, DavideMereu, ElisabettaBullich, GemmaThompson, RachelHorvath, RitaPérez-Jurado, Luis AlbertoRiess, OlafGut, Ivovan Ommen, Gert-JanLochmüller, HannsBeltran, SergiRD–Connect Genome-Phenome Analysis PlatformURD-Cat Data ContributorsPosada De la Paz, ManuelHomozygoteConsanguinityExomeGenome, HumanHumansModels, GeneticMolecular Diagnostic TechniquesPedigreePolymorphism, Single NucleotideRare DiseasesExome SequencingAutozygosity 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.ElsevierUnión Europea. Comisión Europea. H2020Instituto de Salud Carlos IIIUnión Europea. Comisión Europea. 7 Programa MarcoGovernment of Catalonia (España)Canadian Institutes of Health ResearchUnión Europea. Comisión Europea. European Research Council (ERC)Medical Research Council (Reino Unido)Wellcome TrustMinisterio de Economía, Industria y Competitividad (España)European Molecular Biology LaboratoryMinisterio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España)Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)Wellcome Investigator20232023-03-0320202020-09-0120202020-09-01research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/20.500.12105/15568reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)InglésengEuropean Commission http://dx.doi.org/10.13039/501100000780 Seventh Framework Programme 305444European Commission http://dx.doi.org/10.13039/501100000780 Horizon 2020 Framework Programme 779257European Commission http://dx.doi.org/10.13039/501100000780 Horizon 2020 Framework Programme 825575European Commission http://dx.doi.org/10.13039/501100000780 Seventh Framework Programme 313010European Commission http://dx.doi.org/10.13039/501100000780 Seventh Framework Programme 305121European Commission http://dx.doi.org/10.13039/501100000780 Seventh Framework Programme 309548open accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/155682026-06-12T12:43:37Z
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, Leslie Homozygote Consanguinity Exome Genome, Human Humans Models, Genetic Molecular Diagnostic Techniques Pedigree Polymorphism, Single Nucleotide Rare Diseases Exome Sequencing
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, Leslie Laurie, Steven Papakonstantinou, Anastasios Piscia, Davide Mereu, Elisabetta Bullich, Gemma Thompson, Rachel Horvath, Rita Pérez-Jurado, Luis Alberto Riess, Olaf Gut, Ivo van Ommen, Gert-Jan Lochmüller, Hanns Beltran, Sergi RD–Connect Genome-Phenome Analysis Platform URD-Cat Data Contributors Posada De la Paz, Manuel
author	Matalonga, Leslie
author_facet	Matalonga, Leslie Laurie, Steven Papakonstantinou, Anastasios Piscia, Davide Mereu, Elisabetta Bullich, Gemma Thompson, Rachel Horvath, Rita Pérez-Jurado, Luis Alberto Riess, Olaf Gut, Ivo van Ommen, Gert-Jan Lochmüller, Hanns Beltran, Sergi RD–Connect Genome-Phenome Analysis Platform URD-Cat Data Contributors Posada De la Paz, Manuel
author_role	author
author2	Laurie, Steven Papakonstantinou, Anastasios Piscia, Davide Mereu, Elisabetta Bullich, Gemma Thompson, Rachel Horvath, Rita Pérez-Jurado, Luis Alberto Riess, Olaf Gut, Ivo van Ommen, Gert-Jan Lochmüller, Hanns Beltran, Sergi RD–Connect Genome-Phenome Analysis Platform URD-Cat Data Contributors Posada De la Paz, Manuel
author2_role	author author author author author author author author author author author author author author author author
dc.contributor.none.fl_str_mv	Unión Europea. Comisión Europea. H2020 Instituto de Salud Carlos III Unión Europea. Comisión Europea. 7 Programa Marco Government of Catalonia (España) Canadian Institutes of Health Research Unión Europea. Comisión Europea. European Research Council (ERC) Medical Research Council (Reino Unido) Wellcome Trust Ministerio de Economía, Industria y Competitividad (España) European Molecular Biology Laboratory Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España) Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF) Wellcome Investigator
dc.subject.none.fl_str_mv	Homozygote Consanguinity Exome Genome, Human Humans Models, Genetic Molecular Diagnostic Techniques Pedigree Polymorphism, Single Nucleotide Rare Diseases Exome Sequencing
topic	Homozygote Consanguinity Exome Genome, Human Humans Models, Genetic Molecular Diagnostic Techniques Pedigree Polymorphism, Single Nucleotide Rare Diseases Exome Sequencing
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 2020-09-01 2020 2020-09-01 2023 2023-03-03
dc.type.none.fl_str_mv	research article http://purl.org/coar/resource_type/c_2df8fbb1 VoR http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv	info:eu-repo/semantics/article
format	article
dc.identifier.none.fl_str_mv	http://hdl.handle.net/20.500.12105/15568
url	http://hdl.handle.net/20.500.12105/15568
dc.language.none.fl_str_mv	Inglés eng
language_invalid_str_mv	Inglés
language	eng
dc.relation.none.fl_str_mv	European Commission http://dx.doi.org/10.13039/501100000780 Seventh Framework Programme 305444 European Commission http://dx.doi.org/10.13039/501100000780 Horizon 2020 Framework Programme 779257 European Commission http://dx.doi.org/10.13039/501100000780 Horizon 2020 Framework Programme 825575 European Commission http://dx.doi.org/10.13039/501100000780 Seventh Framework Programme 313010 European Commission http://dx.doi.org/10.13039/501100000780 Seventh Framework Programme 305121 European Commission http://dx.doi.org/10.13039/501100000780 Seventh Framework Programme 309548
dc.rights.none.fl_str_mv	open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 Internacional http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv	info:eu-repo/semantics/openAccess
rights_invalid_str_mv	open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 Internacional http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	application/pdf
dc.publisher.none.fl_str_mv	Elsevier
publisher.none.fl_str_mv	Elsevier
dc.source.none.fl_str_mv	reponame:Repisalud instname:Instituto de Salud Carlos III (ISCIII)
instname_str	Instituto de Salud Carlos III (ISCIII)
reponame_str	Repisalud
collection	Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
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Improved Diagnosis of Rare Disease Patients through Systematic Detection of Runs of Homozygosity

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