Abstract of R01 Minority Supplement Studies in whites of European descent have shown that atrial fibrillation (AF) has a strong genetic component especially in probands with early-onset AF. However, the role of family history and the underlying genetic mechanisms for lone (early-onset) atrial flutter (AFL) remain unclear. The major goal of Specific Aim 1 is to determine if African American, European American and Hispanic/Latino probands with early-onset AFL have a higher rate of arrhythmia recurrence in first-degree family members than ethnically-matched patients with late- onset AFL. Patients prospectively recruited in the University of Illinois at Chicago (UIC), Jesse Brown Veterans Administration (JBVA) and Advocate Heart Institute (AHI) AF/AFL Registry who completed a baseline questionnaire detailing clinical characteristics including a family history of AFL in first-degree relatives will form the study cohort. We define early-onset AFL as AFL occurring in a proband ≤66 years of age in the absence of overt structural heart disease by clinical examination, echocardiography and electrocardiogram. All other forms of AFL are categorized as late-onset AFL. A family history of AFL will be verified by ECG confirmation in family members. Although genetic approaches to AF have provided important insights into the pathophysiology and identified novel therapeutic pathways, the underlying genetic mechanisms of AFL remain unclear in part because of the challenges of adequately recapitulating human AFL in cellular models. Specific Aim 2 will identify and phenotypically characterize African American, European American, and Hispanic/Latino kindreds with familial early-onset AFL, identify novel mutations causing the arrhythmia and elucidate the underlying cellular mechanisms using mature atrial iPSC-CMs (as described in the parent grant). Our studies will not only determine for the first time the role of family history in the pathogenesis of early-onset AFL and identify novel genes and mutations but also elucidate the underlying cellular mechanisms and identify potential mechanism- based therapies for this common and morbid arrhythmia across race-ethnicity.