Genetic Testing Identifies Disease-Associated Variants in Patients with AFib


Overall positive genetic test results for variants was 10.1% for patients diagnosed with AF before 66 years of age and 16.8% in patients diagnosed before 30 years of age.

M. Benjamin Shoemaker, MD

M. Benjamin Shoemaker, MD

Although genetic testing does not have current recommendations for patients with atrial fibrillation (AF), new data suggests patients with early-onset AF are enriched for rare disease-associated variants.

As a result, a recent study examined results of genetic testing for early-onset AF, in order to compare frequency of disease-associated variants by age at diagnosis, specificity in the inherited syndromes, and individual genes.

The team of investigators, led by M. Benjamin Shoemaker, MD, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, found genetic testing helped identify a disease-associated variant in 10% of the targeted patient population with early-onset AF.


Participants in the study were patients with early-onset AF, with a definition of diagnosis before the age of 66 years. They were enrolled from November 1999 - June 2015, with analysis taking place from October 2020 - March 2021.

Further, patients who were eligible for study enrollment underwent whole genome sequencing in the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine.

A panel of 145 genes included on cardiomyopathy and arrhythmia panels used by commercial clinical genetic testing laboratories were used in the study.

Investigators assigned genes for disease-associated variants to a specific syndrome, including arrhythmogenic cardiomyopathy/arrhythmogenic right ventricular cardiomyopathy (AC/ARVC), Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT), dilated cardiomyopathy, HCM, and LQTS.

The primary outcome included classification of rare variants through the American College of Medical Genetics and Genomics criteria, including benign, likely benign, variant of undetermined significance (VUS), likely pathogenic, or pathogenic.

Accordingly, disease-associated variants were defined as pathogenic or likely pathogenic variants in genes associated with autosomal dominant or X-linked dominant disorders.


A total of 1293 participants were included in the study, with 934 male (72.2%), with a median age of 56 years at enrollment and median age of 50 years at AF diagnosis. The study included a majority of White participants (95.7%).

Data show participants with disease-associated variants were more likely to have history of heart failure (n = 36), in comparison to other groups (P = .001).

Investigators placed participants in mutually exclusive groups according to variant status for a total of 4 groups.

The first group consisted of participants considered to be carrying a disease-associated variant, with 131 members (10.1%) of the total study population.

Further, group 2 consisted of 812 participants (62.8%) of the total cohort, with a VUS and group 3 consisted of 92 participants (7.1%) as heterozygous carriers of an autosomal recessive disorder. Lastly, 258 participants (20.0%) had no suspicious variant according to investigators.

Data show the number of disease-associated variants was highest in participants diagnosed with AF before the age of 30 years (20 of 119, 16.8%; 95% CI, 10.0% - 23.6%). The number of disease-associated variants was shown to be lowest in patients aged 60 - 65 years (8 of 112, 7.1%; 95% CI, 2.4% - 11.9%).

Investigators noted disease-associated variants had more associations with genes in inherited cardiomyopathy syndromes compared to inherited arrhythmia syndromes. Data show the number of participants with disease-associated rare variants included 93 (7.2%) for DCM, 43 (3.3%) for HCM, and 37 (2.9%) for AC/ARVC.

Out of the total 141 P/LP variants, the genes with the most prevalent group 1 variants included 38 (27%) in TTN, 18 (13%) in MYH7, 10 (7%) in MYH6, 9 (6%) in LMNA, and 8 (6%) in KCNQ1.


Investigators concluded disease-associated variants were more common in genes associated with cardiomyopathies, including DCM, HCM, and AC/ARVC, in comparison to channelopathies, including LQTS and Brugada syndrome.

“An important future question is to what degree patients with early- onset AF attributable to a cardiomyopathy-associated variant will develop heart failure, ventricular arrhythmias, and stroke and whether early identification may present the opportunity to modify the progression of disease and indicate the need for more aggressive control of traditional clinical risk factors,” investigators wrote.

The study, “Early-Onset Atrial Fibrillation and the Prevalence of Rare Variants in Cardiomyopathy and Arrhythmia Genes,” was published online in JAMA Cardiology.

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