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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Published in:The Journal of molecular diagnostics : JMD 2020-09, Vol.22 (9), p.1205-1215
Main Authors: Matalonga, Leslie, 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, Beltran, Sergi, Renieri, Alessandra, Dursun, Ali, Matilla-Duenas, Antoni, Cormand, Bru, Rivolta, Carlo, Ayuso, Carmen, Espinós, Carmen, Scerri, Christian, Yalnizoglu, Dilek, Soler, Doriette, Morava, Eva, Barbetti, Fabrizio, Forzano, Francesca, Mari, Francesca, Muntoni, Francesco, Tort, Frederic, Houlden, Henry James, Tejada, Maria-Isabel, Senderek, Jan, Benitez, Javier, De La Calle, Javier Corral, Serra, Jordi, Millán, José Ma, Segovia, Jose, Gimeno Blanes, Juan Ramon, Armstrong, Judith, Ozgul, Koksal, Vilarinho, Laura, Montoliu, Lluis, Posada, Manuel, Mencarelli, Maria Antonietta, Mora, Marina, Bianchi, Paola, Seeman, Pavel, Elliott, Perry M., Ferlini, Alessandra, Brice, Alexis, Wirth, Brunhilde, Hanna, Mike, Tabrizi, Sarah, Klockgether, Thomas, Timmerman, Vincent, Straub, Volker, Kurul, Semra Hiz, Oktay, Yavuz, Gungor, Serdal, Yaramis, Ahmet, Yis, Uluc, Macaya, Alfons, Ribes, Antonia, Pujol, Aurora, Lázaro, Conxi, Grinberg, Daniel, Tizzano, Eduardo, Cardellach, Francesc, Palau, Francesc, Milà, Montse, Gallano, Pia, Artuch, Rafael, MartiSeves, Ramon, Villanueva, Gonzalo, Vidal, Silvia, Garrabou, Gloria, Balcells, Susanna, Urreizti, Roser, López, Estrella, Cuscó, Ivon, Valenzuela, Irene, Sabater, Maria
Format: Article
Language:English
Subjects:
Consanguinity
Exome
Exome Sequencing - methods
Genome, Human
Homozygote
Humans
Models, Genetic
Molecular Diagnostic Techniques - methods
Pedigree
Polymorphism, Single Nucleotide
Rare Diseases - diagnosis
Rare Diseases - epidemiology
Rare Diseases - ethnology
Rare Diseases - genetics
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Summary: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.
ISSN:1525-1578
1943-7811
DOI:10.1016/j.jmoldx.2020.06.008