Thursday, April 3, 2025
4/3/2025
Investigating structural and genetic substrates of early-onset atrial fibrillation - PROJECT SUMMARY/ABSTRACT Early-onset atrial fibrillation (a first event of atrial fibrillation before 35 years of age) is associated with frequent recurrences, often requiring electrical shocks to stop the arrhythmia, medication to prevent arrhythmia or surgical/interventional management. Recent work has demonstrated that adult interventions for atrial fibrillation (AF) are not effective in changing the frequency of recurrence in children and young adults. In clinical practice, pediatric cardiologists do not follow the AF recommendations designed for adults. Recommendations for therapy have not been established in early-onset AF, in part because we may be currently assessing the wrong markers for risk. Our central hypothesis is that identifiable genetic factors are associated with clinical recurrence in children and young adults with AF at ≤ 35 years of age. We will use three genomic approaches to addressing our central hypothesis: a validated gene panel (Aim 1), common-variant analysis (Aim 2A), and rare variant analysis with whole genome sequencing (Aim 2B). We will recruit patients with early-onset AF in a multicenter network. In a prospective, observational study, we will record phenotype information and obtain genetic material. In our first aim, we will determine if patients with pathogenic and likely pathogenic (P/LP) variants in 311 established cardiac genes have a shorter time to first AF recurrence than patients without a P/LP variant. By testing clinically relevant genes in commercially available panels, we will be able to rapidly translate the results of our first aim to clinical practice. In the second aim, we will focus on new genomic relationships. Data from genome-wide association studies of AF in older adults have generated polygenic risk scores (PRS). High scores on PRS have been associated with increased morbidity and mortality in older adults. However, it is not known whether AF PRS have any relevance in children and young adults, nor whether they are markers of lifelong genomic and myopathic risk. Therefore, we will validate whether existing AF PRS are higher in early-onset AF than in a control population without cardiac phenotype. Finally, in a second genomic analysis, we identify probands who have no P/LP variants in Aim 1 of the study. From those P/LP-negative probands, we will identify trios where the proband has early-onset AF and both parents are negative for cardiac disease with a negative family history of early-onset AF. We will perform trio whole genome sequencing to identify novel genetic markers of risk in early-onset AF. If our central hypothesis is correct, these three approaches will identify a novel set of risk factors in early-onset AF. The immediate impact will be the ability to test for commercially available genetic abnormalities that identify risk of early AF recurrence and that may identify lifelong risk for progression of myopathy, with implications for therapy and prevention. As a secondary benefit, the identification of P/LP variants in a proband has implications for cascade screening in families. Finally, work on the genomic underpinnings of early-onset AF has implications not only in the young, but as a hypothesis that the lifelong risks of atrial myopathy affect the later incidence of atrial fibrillation in older adults.
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