Detection of pathogenic genetic variants in early-onset atrial fibrillation

1. Genetic testing in patients with early-onset atrial fibrillation, via major commercial arrhythmia and cardiomyopathy gene panels, were able to detect a disease-associated variant in approximately 10% of patients, with a higher rate in those diagnosed before the age of 30 years.

2. Disease-associated variants in atrial fibrillation were more common in genes associated with inherited cardiomyopathies than inherited channelopathies.

Evidence Rating Level: 2 (Good)

Study Rundown: Atrial fibrillation (AF) is the most common type of supraventricular tachyarrhythmia where the mainstay of diagnosis and monitoring focuses on the assessment of cardiac rhythm, structure, and function. Currently, genetic testing is not recommended in patients with AF. However, recent data has suggested that early-onset AF may be suggestive of a more serious underlying inherited cardiomyopathy or arrhythmia syndrome. This cohort study analyzed genes currently included on major commercial arrhythmia and cardiomyopathy gene panels to evaluate the frequency of disease-associated variants according to age, specific inherited syndromes, and individual genes. The main endpoint of the analysis was classification of rare variants using American College of Medical Genetics and Genomics (ACMG) criteria: benign, likely benign, variant of undetermined significance, likely pathogenic, or pathogenic. Among 1,293 patients with early-onset AF who underwent whole genome sequencing, disease-associated variants in cardiomyopathy and arrhythmia genes were identified in 10.1% of patients younger than 66 years and 16.8% of individuals younger than 30 years. Furthermore, disease-associated variants were more prevalent in genes associated with inherited cardiomyopathy syndromes than inherited arrhythmia syndromes. These findings suggested that genetic testing in patients with early-onset AF via major commercial arrhythmia and cardiomyopathy gene panels were able to detect a disease-associated variant in approximately 10% of patients, with a higher rate in those diagnosed before the age of 30 years. These results are encouraging in supporting the use of genetic testing in patients presenting with early-onset AF. A limitation of this study was that the patient cohort was consisted predominately of people of European descent where the prevalence of rare variants associated with AF in individuals of underrepresented ethnicities is unclear. Further study is needed on these other ethnic groups to help stratify risk associated with ethnicity and increase generalizability of the study’s findings.

Click to read the study in JAMA Cardiology

Click to read an accompanying editorial in JAMA Cardiology

Relevant Reading: Broad genetic testing in a clinical setting uncovers a high prevalence of titin loss-of-function variants in very early onset atrial fibrillation

In-Depth [prospective cohort]: This prospective, single-center, observational cohort study included 1,293 patients with AF (934 [72.2%] male; median [IQR] age at enrollment, 56 [48-61] years; median [IQR] age at AF diagnosis, 50 [41-56] years) diagnosed before 66 years of age from November 1999 to June 2015 and underwent whole genome sequencing through the National Heart, Lung, and Blood Institute’s Trans-Omics for Precision Medicine program. Data analysis was performed between October 2020 and March 2021 where sequencing data from commercial cardiomyopathy and arrhythmia panels (145-gene panel) were analyzed using an automated process followed by manual review by a panel of independent, blinded reviewers. In total, genetic testing identified 131 patients (10.1%) with a disease-associated variant, 812 (62.8%) with a variant of undetermined significance, 92 (7.1%) as heterozygous carriers for an autosomal recessive disorder, and 258 (20.0%) with no suspicious variant. Disease-associated variants were most prevalent in patients diagnosed before the age of 30 years (20 of 119 [16.8%; 95%CI, 10.0%-23.6%]) and lowest after the age of 60 years (8 of 112 [7.1%; 95%CI, 2.4%-11.9%]). Lastly, disease-associated variants were most common in genes associated with inherited cardiomyopathy syndromes than inherited arrhythmia syndromes, where the most affected genes were TTN (n = 38), MYH7 (n = 18), MYH6 (n = 10), LMNA (n = 9), and KCNQ1 (n = 8).

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