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

ABSTRACT: 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.

SUBMITTER: Mates J

PROVIDER: S-EPMC6018743 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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

Mates Jesus J Mademont-Soler Irene I Del Olmo Bernat B Ferrer-Costa Carles C Coll Monica M Pérez-Serra Alexandra A Picó Ferran F Allegue Catarina C Fernandez-Falgueras Anna A Álvarez Patricia P Yotti Raquel R Espinosa Maria Angeles MA Sarquella-Brugada Georgia G Cesar Sergi S Carro Ester E Brugada Josep J Arbelo Elena E Garcia-Pavia Pablo P Borregan Mar M Tizzano Eduardo E López-Granados Amador A Mazuelos Francisco F Díaz de Bustamante Aranzazu A Darnaude Maria Teresa MT González-Hevia José Ignacio JI Díaz-Flores Felícitas F Trujillo Francisco F Iglesias Anna A Fernandez-Aviles Francisco F Campuzano Oscar O Brugada Ramon R

European journal of human genetics : EJHG 20180306 7

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 (car ...[more]

PMID: 29511324

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Project description:BACKGROUND:Sudden cardiac death occurs in ?220,000 U.S. adults annually, the majority of whom have no prior symptoms or cardiovascular diagnosis. Rare pathogenic DNA variants in any of 49 genes can pre-dispose to 4 important causes of sudden cardiac death: cardiomyopathy, coronary artery disease, inherited arrhythmia syndrome, and aortopathy or aortic dissection. OBJECTIVES:This study assessed the prevalence of rare pathogenic variants in sudden cardiac death cases versus controls, and the prevalence and clinical importance of such mutations in an asymptomatic adult population. METHODS:The authors performed whole-exome sequencing in a case-control cohort of 600 adult-onset sudden cardiac death cases and 600 matched controls from 106,098 participants of 6 prospective cohort studies. Observed DNA sequence variants in any of 49 genes with known association to cardiovascular disease were classified as pathogenic or likely pathogenic by a clinical laboratory geneticist blinded to case status. In an independent population of 4,525 asymptomatic adult participants of a prospective cohort study, the authors performed whole-genome sequencing and determined the prevalence of pathogenic or likely pathogenic variants and prospective association with cardiovascular death. RESULTS:Among the 1,200 sudden cardiac death cases and controls, the authors identified 5,178 genetic variants and classified 14 as pathogenic or likely pathogenic. These 14 variants were present in 15 individuals, all of whom had experienced sudden cardiac death-corresponding to a pathogenic variant prevalence of 2.5% in cases and 0% in controls (p < 0.0001). Among the 4,525 participants of the prospective cohort study, 41 (0.9%) carried a pathogenic or likely pathogenic variant and these individuals had 3.24-fold higher risk of cardiovascular death over a median follow-up of 14.3 years (p = 0.02). CONCLUSIONS:Gene sequencing identifies a pathogenic or likely pathogenic variant in a small but potentially important subset of adults experiencing sudden cardiac death; these variants are present in ?1% of asymptomatic adults.

Project description:ImportanceUnexplained sudden cardiac death (SCD) describes SCD with no cause identified. Genetic testing helps to diagnose inherited cardiac diseases in unexplained SCD; however, the associations between pathogenic or likely pathogenic (P/LP) variants of inherited cardiomyopathies (CMs) and arrhythmia syndromes and the risk of unexplained SCD in both White and African American adults living the United States has never been systematically examined.ObjectiveTo investigate cases of unexplained SCD to determine the frequency of P/LP genetic variants of inherited CMs and arrhythmia syndromes.Design, setting, and participantsThis genetic association study included 683 African American and White adults who died of unexplained SCD and were included in an autopsy registry. Overall, 413 individuals had DNA of acceptable quality for genetic sequencing. Data were collected from January 1995 to December 2015. A total of 30 CM genes and 38 arrhythmia genes were sequenced, and variants in these genes, curated as P/LP, were examined to study their frequency. Data analysis was performed from June 2018 to March 2021.Main outcomes and measuresThe frequency of P/LP variants for CM or arrhythmia in individuals with unexplained SCD.ResultsThe median (interquartile range) age at death of the 413 included individuals was 41 (29-48) years, 259 (62.7%) were men, and 208 (50.4%) were African American adults. A total of 76 patients (18.4%) with unexplained SCD carried variants considered P/LP for CM and arrhythmia genes. In total, 52 patients (12.6%) had 49 P/LP variants for CM, 22 (5.3%) carried 23 P/LP variants for arrhythmia, and 2 (0.5%) had P/LP variants for both CM and arrhythmia. Overall, 41 P/LP variants for hypertrophic CM were found in 45 patients (10.9%), 9 P/LP variants for dilated CM were found in 11 patients (2.7%), and 10 P/LP variants for long QT syndrome were found in 11 patients (2.7%). No significant difference was found in clinical and heart characteristics between individuals with or without P/LP variants. African American and White patients were equally likely to harbor P/LP variants.Conclusions and relevanceIn this large genetic association study of community cases of unexplained SCD, nearly 20% of patients carried P/LP variants, suggesting that genetics may contribute to a significant number of cases of unexplained SCD. Our findings regarding both the association of unexplained SCD with CM genes and race-specific genetic variants suggest new avenues of study for this poorly understood entity.

Dataset Information

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

Publications

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

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