Abstract
Introduction
Mutations in cardiac ion channels, structural proteins and signaling molecules have been identified in European whites with early-onset AF (EOAF). However, it remains unclear if genetic variation also contributes to the etiology of EOAF in ethnic minorities.
Purpose
To determine the prevalence of disease causing variants in candidate AF genes in African American and Hispanic/Latino probands with EOAF.
Method
In this family-based study, probands of African and Hispanic descent with EOAF (defined as AF ≤65 years) were prospectively enrolled in a clinical-DNA biorepository and underwent targeted sequencing for 60 AF candidate genes. Variants were filtered at 20X read depth and clinically evaluated with American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) as well as the Association for Clinical Genomic Science (ACGS) criteria for disease-causing mutations.
Results
Among 227 EOAF probands with mean (SD) age of AF 51.0 (9.9) years, 132 (58.0%) were men and 148 (65.0%) African American and 79 (35.0%) Hispanic/Latino. Sequencing 60 candidate AF genes revealed 90 variants that met filtering criteria and underwent clinical evaluation. We identified 16 (7.0%) EOAF probands with a likely pathogenic or pathogenic variant with the majority being loss of function (62.5%) and located in the TTN gene (50.0%). We confirmed a family history of AF in 24 probands (10.6%) and 6 families with >1 affected member a variant of unknown significance (VUS) in genes encoding for a sodium channel (SCN10A), potassium channel (KCNE5), sarcomeric proteins (MYH6, TTN) and atrial natriuretic peptide (NPPA) co-segregated with AF.
Conclusion
Gene sequencing in African American and Hispanic/Latinos probands with EOAF identified a small percentage of disease causing variants in patients with EOAF. Our findings not only represent important progress toward molecular phenotyping of EOAF, but also provides insight into the underlying pathophysiology toward targeted mechanism-based therapies for AF in ethnic minorities.
Funding Acknowledgement
Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): American Heart Association
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