Abstract 18478: Association of Family History and Cardiomyopathy-Associated Gene Variants of Unknown Significance in Ethnic Minority Patients With Early Onset Atrial Fibrillation

Introduction: Underrepresentation of ethnic minorities in genetic studies can complicate interpretation of variants of unknown significance (VUS) in these groups. Likely pathogenic or pathogenic (LP/P) cardiomyopathy (CM) gene variants are associated with early onset-atrial fibrillation (EOAF) in a cohort of predominantly European ancestry, but prevalence in minorities, and the role of VUS, is unclear. Three-generation family history (FH) may provide insight into the potential pathogenicity of VUS in ethnic minorities.

Hypothesis: In patients with EOAF and low comorbidity burden carrying CM VUS, does positive FH suggest variant pathogenicity?

Aims: To determine whether CM gene VUS in ethnic minority probands with EOAF are associated with a FH of arrhythmia, stroke, or heart failure.

Methods: Of 301 individuals from the University of Illinois Health Multi-Ethnic AF Registry who underwent whole exome sequencing, we identified 89 with either LP/P variant, positive FH from medical records, or AF diagnosis age ≤55 years and ≤2 comorbidities. We examined 22 genes strongly associated with CM and graded pathogenicity according to American College of Medical Genetics criteria. A three-generation FH was obtained by contacting probands or family members.

Results: A FH was obtained in 36 patients (Figure 1a; median age 52 years, 56% female, 83% African-American, 17% Hispanic/Latinx). LP/P variants were present in 3 (8%) probands, VUS in 10 (28%), and likely benign/benign (LB/B) or no variant in 23 (64%). A FH of arrhythmia, heart failure, or stroke was present in 27 subjects (75%) with a FH of heart failure more likely in VUS carriers compared to those with LB/B or no variant (70% vs 26%, p=0.02), with no difference in FH of arrhythmia or stroke.

Conclusion: Probands with EOAF who carry CM VUS have greater rates of FH of heart failure than those without disease-associated variants. This suggests pathogenicity of CM VUS in ethnic minorities with EOAF.