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.
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.
Authors: Melissa Anfinson; Robert H Fitts; John W Lough; Jeanne M James; Pippa M Simpson; Stephanie S Handler; Michael E Mitchell; Aoy Tomita-Mitchell Journal: J Cardiovasc Dev Dis Date: 2022-05-03
Authors: Kamala P Tamirisa; Sana M Al-Khatib; Sanghamitra Mohanty; Janet K Han; Andrea Natale; Dhiraj Gupta; Andrea M Russo; Amin Al-Ahmad; Anne M Gillis; Kevin L Thomas Journal: CJC Open Date: 2021-09-13
Authors: Zachary T Yoneda; Katherine C Anderson; Fei Ye; Joseph A Quintana; Matthew J O'Neill; Richard A Sims; Lili Sun; Andrew M Glazer; Giovanni Davogustto; Majd El-Harasis; James L Laws; Brittany N Saldivar; Diane M Crawford; Thomas Stricker; Quinn Wells; Dawood Darbar; Gregory F Michaud; Lynne W Stevenson; Steven A Lubitz; Patrick T Ellinor; Dan M Roden; M Benjamin Shoemaker Journal: JAMA Cardiol Date: 2022-07-01 Impact factor: 30.154
Authors: Iqbal El Assaad; Benjamin H Hammond; Lukas D Kost; Sarah Worley; Christopher M Janson; Elizabeth D Sherwin; Elizabeth A Stephenson; Christopher L Johnsrude; Mary Niu; Ira Shetty; David Lawrence; Anthony C McCanta; Seshadri Balaji; Shubhayan Sanatani; Frank Fish; Gregory Webster; Peter F Aziz Journal: Heart Rhythm Date: 2021-07-31 Impact factor: 6.779