Improved diagnosis of rare disease patients through systematic detection of runs of homozygosity
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- dc.contributor.author Matalonga, Leslie
- dc.contributor.author Laurie, Steven, 1973-
- dc.contributor.author Papakonstantinou, Anastasios
- dc.contributor.author Piscia, Davide
- dc.contributor.author Mereu, Elisabetta
- dc.contributor.author Bullich, Gemma
- dc.contributor.author Thompson, Rachel
- dc.contributor.author Horvath, Rita
- dc.contributor.author Pérez Jurado, Luis Alberto
- dc.contributor.author Riess, Olaf
- dc.contributor.author Gut, Ivo Glynne
- dc.contributor.author van Ommen, Gert-Jan
- dc.contributor.author Lochmüller, Hanns
- dc.contributor.author Beltran, Sergi
- dc.contributor.author RD–Connect Genome-Phenome Analysis Platform and URD-Cat Data Contributors
- dc.date.accessioned 2020-10-13T09:29:15Z
- dc.date.available 2020-10-13T09:29:15Z
- dc.date.issued 2020
- dc.description.abstract 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.
- dc.description.sponsorship Supported by European Union projects RD-Connect, Solve-RD, and European Joint Programme of Rare Diseases (EJP-RD) grants FP7 305444, H2020 779257, and H2020 825575; Instituto de Salud Carlos III grants PT13/0001/0044 and PT17/0009/0019; Instituto Nacional de Bioinformática; ELIXIR Implementation Studies; European Union projects BBMRI-LPC EU FP7 313010, NeurOmics EU FP7 305121, and Undiagnosed Rare Disease Program of Catalonia (Departament de Salut, Generalitat de CatalunyaSLT002/16/00174); Canadian Institutes of Health Research Foundation grant FDN-167281 (H.L.); the European Research Council309548 (R.H.); the Wellcome Investigator Award 109915/Z/15/Z (R.H.); the Medical Research Council (United Kingdom) MR/N025431/1 (R.H.); the Wellcome Trust Pathfinder Scheme 201064/Z/16/Z (R.H. and H.L.); the Newton Fund (United Kingdom/Turkey) MR/N027302/1 (R.H. and H.L.); the Spanish Ministry of Economy, Industry and Competitiveness to the European Molecular Biology Laboratory (EMBL) partnership; the Centro de Excelencia Severo Ochoa; the Centres de Recerca de Catalunya (CERCA) Program/Generalitat de Catalunya; the Generalitat de Catalunya through the Department of Health and Department of Business and Knowledge; the Spanish Ministry of Economy, Industry and Competitiveness with funds from the European Regional Development Fund corresponding to the 2014 to 2020 Smart Growth Operating Program.
- dc.format.mimetype application/pdf
- dc.identifier.citation Matalonga L, Laurie S, Papakonstantinou A, Piscia D, Mereu E, Bullich G. et al. Improved diagnosis of rare disease patients through systematic detection of runs of homozygosity. J Mol Diagn. 2020 Sep; 22(9):1205-15. DOI: 10.1016/j.jmoldx.2020.06.008
- dc.identifier.doi http://dx.doi.org/10.1016/j.jmoldx.2020.06.008
- dc.identifier.issn 1525-1578
- dc.identifier.uri http://hdl.handle.net/10230/45468
- dc.language.iso eng
- dc.publisher Elsevier
- dc.relation.ispartof The Journal of Molecular Diagnostics. 2020 Sep;22(9):1205-15
- dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/305444
- dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/779257
- dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/825575
- dc.rights Copyright © 2020 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
- dc.rights.accessRights info:eu-repo/semantics/openAccess
- dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
- dc.subject.other Malalties rares
- dc.subject.other Embriologia
- dc.subject.other Genètica
- dc.title Improved diagnosis of rare disease patients through systematic detection of runs of homozygosity
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion