Role of copy number variants in sudden cardiac death and related diseases: genetic analysis and translation into clinical practice

• Published in: European journal of human genetics : EJHG Vol. 26; no. 7; pp. 1014 - 1025
• Main Authors: Mates, Jesus, Mademont-Soler, Irene, Del Olmo, Bernat, Ferrer-Costa, Carles, Coll, Monica, Pérez-Serra, Alexandra, Picó, Ferran, Allegue, Catarina, Fernandez-Falgueras, Anna, Álvarez, Patricia, Yotti, Raquel, Espinosa, Maria Angeles, Sarquella-Brugada, Georgia, Cesar, Sergi, Carro, Ester, Brugada, Josep, Arbelo, Elena, Garcia-Pavia, Pablo, Borregan, Mar, Tizzano, Eduardo, López-Granados, Amador, Mazuelos, Francisco, Díaz de Bustamante, Aranzazu, Darnaude, Maria Teresa, González-Hevia, José Ignacio, Díaz-Flores, Felícitas, Trujillo, Francisco, Iglesias, Anna, Fernandez-Aviles, Francisco, Campuzano, Oscar, Brugada, Ramon
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01-07-2018; Springer International Publishing
• Subjects: Cardiomyopathy; Channelopathy; Copy number; Coronary artery disease; Death; Defibrillators; Dilated cardiomyopathy; Genetic analysis; Genetic screening; Heart diseases; Long QT syndrome; Next-generation sequencing
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/s41431-018-0119-1

Several studies have identified copy number variants (CNVs) as responsible for cardiac diseases associated with sudden cardiac death (SCD), but very few exhaustive analyses in large cohorts of patients have been performed, and they have been generally focused on a specific SCD-related disease. The aim of the present study was to screen for CNVs the most prevalent genes associated with SCD in a large cohort of patients who suffered sudden unexplained death or had an inherited cardiac disease (cardiomyopathy or channelopathy). A total of 1765 European patients were analyzed with a homemade algorithm for the assessment of CNVs using high-throughput sequencing data. Thirty-six CNVs were identified (2%), and most of them appeared to have a pathogenic role. The frequency of CNVs among cases of sudden unexplained death, patients with a cardiomyopathy or a channelopathy was 1.4% (8/587), 2.3% (20/874), and 2.6% (8/304), respectively. Detection rates were particularly high for arrhythmogenic cardiomyopathy (5.1%), long QT syndrome (4.7%), and dilated cardiomyopathy (4.4%). As such large genomic rearrangements underlie a non-neglectable portion of cases, we consider that their analysis should be performed as part of the routine genetic testing of sudden unexpected death cases and patients with SCD-related diseases.