ScholarLens Back to search
2020•Journal of Molecular DiagnosticsOpen access

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

Leslie Matalonga, Steven Laurie, Anastasios Papakonstantinou, Davide Piscia, Elisabetta Mereu, Gemma Bullich, Rachel Thompson, Rita Horváth, Luis A. Pérez‐Jurado, Olaf Rieß, Marta Gut, Gert‐Jan B. van Ommen, Hanns Lochmüller, Sergi Beltrán, Alessandra Renieri, Ali Dursun, Antoni Matilla‐Dueñas, Bru Cormand, Carlo Rivolta, Carmen Ayuso, Carmen Espinós, Christian Scerri, Dilek Yalnızoğlu, Doriette Soler, Éva Morava, Fabrizio Barbetti, Francesca Forzano, Francesca Mari, Francesco Muntoni, Frederic Tort, Henry Houlden, María‐Isabel Tejada, Jan Senderek, Javier Benı́tez, Javier Corral De La Calle, Jordi Serra, José M. Millán, José Carlos Segovia, Juan Ramón Gimeno Blanes, Judith Armstrong, Koksal Ozgul, Laura Vilarinho, Lluı́s Montoliu, Manuel Posada, Maria Antonietta Mencarelli, Marina Mora, Paola Bianchi, Pavel Seeman, Perry Elliott, Alessandra Ferlini, Alexis Brice, Brunhilde Wirth, Francesco Muntoni, Mike Hanna, Sarah J. Tabrizi, Thomas Klockgether, Vincent Timmerman, Volker Straub, Semra Hız Kurul, Yavuz Oktay, Serdal Güngör, Ahmet Yaramış, Uluç Yiş, Alfons Macaya, Antònia Ribes, Aurora Pujol, Conxi Lázaro, Daniel Grinberg, Eduardo F. Tizzano, Francesc Cardellach, Francesc Palau, Montserrat Milà, P. Gallano, Rafael Artuch, Ramon MartiSeves, Gonzalo Villanueva, Silvia M. Vidal, Glòria Garrabou, Susana Balcells, Roser Urreizti, Estrella López, Ivon Cuscó, Irene Valenzuela, Maria Sabater

Open full text 35 citations

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.

Open-access reader

About this research paper

What this paper is about

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.

Why it matters

OpenAlex reports 35 citations for this work. Citation counts describe recorded attention and do not establish research quality.

Key contribution

A contribution statement is not available in the OpenAlex record.

Method / approach

Method details are not available in the OpenAlex metadata.

Main findings

Findings are not separately available in the OpenAlex metadata.

Limitations

Limitations are not available in the OpenAlex metadata.

Applications

Application details are not available in the OpenAlex metadata.

Available 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.

Key concepts: Consanguinity, Runs of Homozygosity, Exome sequencing, Disease gene identification, Exome, Inbreeding, Biology, Genetics

Related papers

Related paper 1Related paper 2Related paper 3
Back to paper searchBrowse research topicsOriginal source
Improved Diagnosis of Rare Disease Patients through Systematic Detection of Runs of Homozygosity — Research Paper | ScholarLens