DOI: 10.1161/circ.148.suppl_1.18478 ISSN: 0009-7322

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

Ashwini Deshpande, Michael Hill, Jood Dabbas, Shashank Sandu, Peter Boxley, Joshua Arnold, Victor Qiao, Brandon Chalazan, David Tofovic, Dawood Darbar
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

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.

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