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Title: Improved diagnosis of rare disease patients through systematic detection of runs of homozygosity
Author: Matalonga Borrel, Lesley
Laurie, Steven
Papakonstantinou, Anastasios
Piscia, Davide
Mereu, Elisabetta
Bullich, Gemma
Thompson, Rachel
Horvath, Rita
Pérez Jurado, Luis
Riess, Olaf
Gut, Ivo
van Ommen, Gert Jan
Lochmüller, Hanns
Beltrán, Sergi
RD-Connect Genome-Phenome Analysis Platform and UR
Cormand Rifà, Bru
Balcells Comas, Susana
Grinberg Vaisman, Daniel Raúl
Urreizti, Roser
Garrabou Tornos, Glòria
Keywords: Malalties hereditàries
Endogàmia i exogàmia
Genetic diseases
Endogamy and exogamy
Issue Date: 1-Sep-2020
Publisher: American Society for Investigative Pathology and the Association for Molecular Pathology
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
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It is part of: Journal of Molecular Diagnostics, 2020, vol. 22, num. 9, p. 1205-1215
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ISSN: 1525-1578
Appears in Collections:Articles publicats en revistes (Genètica, Microbiologia i Estadística)

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