Journal
JOURNAL OF MOLECULAR DIAGNOSTICS
Volume 22, Issue 9, Pages 1205-1215Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jmoldx.2020.06.008
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Funding
- European Union
- European Joint Programme of Rare Diseases (EJP-RD) [FP7 305444, H2020 779257, H2020 825575]
- Instituto de Salud Carlos III [PT13/0001/0044, PT17/0009/0019]
- Instituto Nacional de Bioinformatica
- ELIXIR Implementation Studies
- European Union [313010, 305121]
- Undiagnosed Rare Disease Program of Catalonia (Departament de Salut, Generalitat de Catalunya) [SLT002/16/00174]
- Canadian Institutes of Health Research Foundation [FDN-167281]
- European Research Council [309548]
- Wellcome Investigator Award [109915/Z/15/Z]
- Medical Research Council (United Kingdom) [MR/N025431/1]
- Wellcome Trust Pathfinder Scheme [201064/Z/16/Z]
- Newton Fund (United Kingdom/Turkey) [MR/N027302/1]
- Spanish Ministry of Economy, Industry and Competitiveness
- Centro de Excelencia Severo Ochoa
- Centres de Recerca de Catalunya (CERCA) Program/Generalitat de Catalunya
- Generalitat de Catalunya through the Department of Health and Department of Business and Knowledge
- European Regional Development Fund
- MRC [G1000848, MR/N025431/1, MR/N010035/1, MR/N025431/2] Funding Source: UKRI
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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.
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