Clinical Impact of Pathogenic and Potentially Pathogenic Rare Variants in Ethnic Minorities with Atrial Fibrillation

Background: Rare arrhythmia and cardiomyopathy gene variants have been associated with all-cause mortality among individuals of European ancestry with atrial fibrillation (AF). The prevalence and clinical impact of such variants in racial and ethnic minorities is unknown. Objectives: This study sought to identify the prognostic significance of genetic testing in ethnic minorities with AF from a single urban academic medical center. Methods: A total of 276 Non-Hispanic Black and Hispanic/Latinx individuals with AF underwent whole exome sequencing. Rare likely pathogenic/pathogenic (LP/P) variants and potentially pathogenic variants of uncertain significance (VUS-PP) in arrhythmia and cardiomyopathy genes from standard testing panels were analyzed. The primary outcomes were all-cause mortality and hospitalizations for either AF or acute decompensated heart failure (HF), identified from electronic health records and the National Death Index. Results: LP/P variants were identified in 43 (15.6%) and VUS-PP in 66 (23.9%) of subjects, with TTN the most common gene in which both LP/P variants and VUS-PP were observed. Arrhythmia and cardiomyopathy LP/P variants were associated with increased adjusted all-cause mortality (hazard ratio [HR] 1.67, 95% CI 1.00-2.77, p=0.048), but not adjusted AF/HF hospitalization risk (HR 1.39, 95% CI 0.94-2.06, p=0.098). Examining a subset of dilated/hypertrophic cardiomyopathy genes, both LP/P variants and VUS-PP were associated with elevated adjusted AF/HF hospitalization risk (LP/P: HR 3.51, 95% CI 1.97-6.28, p<0.001; VUS-PP: HR 1.59, 95% CI 1.07-2.36, p=0.022). Conclusions: Rare variants are associated with mortality and hospitalization in an ethnic minority AF cohort. Certain VUS may additionally carry prognostic value in ethnic minorities.