Early-Onset Atrial Fibrillation and the Prevalence of Rare Variants in Cardiomyopathy and Arrhythmia Genes

Abstract

Importance: Early-onset atrial fibrillation (AF) can be the initial manifestation of a more serious underlying inherited cardiomyopathy or arrhythmia syndrome.

Objective: To examine the results of genetic testing for early-onset AF.

Design, setting, and participants: This prospective, observational cohort study enrolled participants from an academic medical center who had AF diagnosed before 66 years of age and underwent whole genome sequencing through the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine program. Participants were enrolled from November 23, 1999, to June 2, 2015. Data analysis was performed from October 24, 2020, to March 11, 2021.

Exposures: Rare variants identified in a panel of 145 genes that are included on cardiomyopathy and arrhythmia panels used by commercial clinical genetic testing laboratories.

Main outcomes and measures: Sequencing data were analyzed using an automated process followed by manual review by a panel of independent, blinded reviewers. The primary outcome was classification of rare variants using American College of Medical Genetics and Genomics criteria: benign, likely benign, variant of undetermined significance, likely pathogenic, or pathogenic. Disease-associated variants were defined as pathogenic/likely pathogenic variants in genes associated with autosomal dominant or X-linked dominant disorders.

Results: Among 1293 participants (934 [72.2%] male; median [interquartile range] age at enrollment, 56 [48-61] years; median [interquartile range] age at AF diagnosis, 50 [41-56] years), genetic testing identified 131 participants (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. The likelihood of a disease-associated variant was highest in participants with AF 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%]). Disease-associated variants were more often associated with inherited cardiomyopathy syndromes compared with inherited arrhythmias. The most common genes were TTN (n = 38), MYH7 (n = 18), MYH6 (n = 10), LMNA (n = 9), and KCNQ1 (n = 8).

Conclusions and relevance: In this cohort study, genetic testing identified a disease-associated variant in 10% of patients with early-onset AF (the percentage was higher if diagnosed before the age of 30 years and lower if diagnosed after the age of 60 years). Most pathogenic/likely pathogenic variants are in genes associated with cardiomyopathy. These results support the use of genetic testing in early-onset AF.

Figure 1.. The Comprehensive Arrhythmia and Cardiomyopathy Gene Panel

Genes were selected from commercial panels. A total of 145 genes were included; 87 were included only on the cardiomyopathy gene panel, 36 only on the arrhythmia gene panel, and 22 on both.

Figure 2.. Results of Genetic Testing in Early-Onset Atrial Fibrillation (AF) for Genes Associated With Arrhythmia and Cardiomyopathy Syndromes

Variants are classified according to standard American College of Medical Genetics and Genomics criteria. AD indicates autosomal dominant; AR, autosomal recessive; P/LP, pathogenic/likely pathogenic; VUS, variant of undetermined significance; XLD, X-linked dominant; XLR, X-linked recessive.

Figure 3.. Prevalence of Disease-Associated Variants and Genetic Overlap With Inherited Cardiomyopathy and Arrhythmia Syndromes

A, Prevalence of disease-associated rare variants according to age at atrial fibrillation (AF) diagnosis presented by age groups. Error bars indicate bootstrapped 95% CIs. B, Prevalence of disease-associated rare variants presented as a continuous variable (cubic spline graph, P = .02 for the association between age and presence of disease-associated variant based on the F test). C, The genetic overlap between disease-associated variants and specific inherited cardiomyopathy and arrhythmia syndromes. Shaded in blue is the proportion of variants in major disease genes for each disorder. AC (ARVC) indicates arrhythmogenic cardiomyopathy (arrhythmogenic right ventricular cardiomyopathy); CPVT, catecholaminergic polymorphic ventricular tachycardia; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; LQTS, long QT syndrome.

Figure 4.. Breakdown According to the Most Prevalent Genes

A, Pathogenic/likely pathogenic (P/LP) variants in autosomal dominant disorders. B, Variants of undetermined significance (VUSs); only loss-of-function variants in TTN are reported. C, Heterozygous P/LP variants in autosomal recessive (AR) disorders.