Association of Rare Genetic Variants and Early-Onset Atrial Fibrillation in Ethnic Minority Individuals

Question What is the prevalence of rare likely pathogenic or pathogenic variants in candidate genes in ethnic minority probands with early-onset atrial fibrillation and genotype-phenotype associations? Findings In this cohort study, a family history of atrial fibrillation was noted in 24 (10.6%) African American and Hispanic/Latinx probands with early-onset atrial fibrillation; sequencing identified 16 (7.0%) probands harboring pathogenic (56.2%) or likely pathogenic (43.8%) variants, with most (46.7%) loss-of-function variants in the TTN gene. In 6 families with more than 2 affected members, variants of unknown significance in cardiac ion channels, sarcomeric proteins, and signaling molecules cosegregated with atrial fibrillation. Meaning Likely pathogenic or pathogenic variants with most loss-of-function variants in TTN that increase susceptibility to atrial fibrillation were observed in African American and Hispanic/Latinx individuals; these findings may provide insights into the underlying pathophysiologic factors and potential mechanism-based therapies for atrial fibrillation in individuals of minority ethnicity. Importance Although rare variants in cardiac ion channels, transcription factors, and myocardial structural proteins are associated with early-onset atrial fibrillation (AF) in White individuals of European descent, it remains unclear whether genetic variation also contributes to the cause of AF in those of minority ethnicity. Objectives To assess the prevalence of rare and novel pathogenic variants in candidate genes in ethnic minority probands with early-onset AF and determine genotype-phenotype associations. Design, Setting, and Participants In this cohort, family-based study, probands of African and Hispanic descent with early-onset AF (defined as AF occurring in individuals aged <= 66 years) prospectively enrolled in a clinical and genetic biorepository underwent sequencing of 60 candidate genes. Recruitment took place from July 1, 2015, to June 30, 2019. Data were analyzed from February 1 to February 28, 2020. Exposures Rare and novel variants categorized as pathogenic or likely pathogenic. Main Outcomes and Measures The prevalence of rare and novel pathogenic variants in African American and Hispanic/Latinx probands with early-onset AF and genotype-phenotype associations. Results Among 227 probands with early-onset AF, mean (SD) age at onset of AF was 51.0 (9.9) years, 132 probands (58.1%) were men, 148 (65.2%) were African American, and 79 (34.8%) were Hispanic/Latinx. A family history of AF was verified in 24 probands with early-onset AF (10.6%). Sequencing 60 candidate genes identified 53 (23 rare and 30 novel) variants with 16 of the 227 (7.0%) probands harboring likely pathogenic (43.8%) or pathogenic (56.2%) variants, with most loss-of-function variants in TTN, the gene encoding the sarcomeric protein titin (46.7%). In 6 families with more than 2 affected members, variants of unknown significance in sodium channel (SCN10A), potassium channel (KCNE5), sarcomeric proteins (MYH6 and TTN), and atrial natriuretic peptide (NPPA) cosegregated with AF. Conclusions and Relevance In this study, likely pathogenic and pathogenic variants were identified, with most loss-of-function variants in TTN, that increase susceptibility to early-onset AF in African American and Hispanic/Latinx individuals. These findings provide further understanding toward molecular phenotyping of AF and suggest novel mechanism-based therapeutic approaches for this common arrhythmia in ethnic minority groups. This cohort study describes comprehensive sequencing of 60 candidate atrial fibrillation genes in African American and Hispanic/Latinx probands to examine the combined prevalence of rare pathogenic variants and assess genotype-phenotype associations.

Automated summary

This cohort study investigated the prevalence of rare likely pathogenic or pathogenic variants in candidate genes in African American and Hispanic/Latinx probands with early-onset atrial fibrillation. Most of the variants were loss-of-function variants in the TTN gene. Variants in other cardiac ion channels, sarcomeric proteins, and signaling molecules co-segregated with atrial fibrillation in some families. These findings may aid in understanding the genetic factors and potential treatments for atrial fibrillation in minority populations.