Abstract 14472: Identifying the Genetic Determinants of Early Heart Failure in Patients with Congenital Heart Disease

Introduction: Heart failure (HF) is the most common cause of death in patients with congenital heart disease (CHD). Evidence suggests genetics play a role in HF predisposition. In particular, variants in cardiomyopathy-associated genes may be associated with HF and early mortality in CHD populations. Goal: Our goal is to leverage a large, well-curated, population-based cohort of individuals with CHD in North Carolina (NC) to determine the genetic underpinnings of HF in CHD. Hypothesis: We hypothesize that rare variants in cardiomyopathy-associated genes will be over-represented in CHD patients with HF compared to patients without HF. Methods: Patients were enrolled with inclusion criteria of 1) presence of CHD, 2) 2+ cardiac evaluations. Whole blood was collected for exome sequencing (ES). The presence of HF was defined as death, cardiac transplantation or listed for cardiac transplantation, VAD placement, ECMO cannulation, EF ≤ 40% on 2 images, or diagnosis of HF by a cardiologist and taking at least 1 HF medication. ES data was filtered for variants in cardiomyopathy-associated genes. Results: We have established NC-DEFINE: Determining the Genetic Basis of Heart Failure in Patients with CHD in NC, a prospectively enrolled cohort of patients with CHD for which ES data are available. We enrolled 138 CHD patients (mean age at enrollment [std dev]: 7.44+/-11.89 years; 40.6% female, 1.4% Asian, 23.9% Black, 6.5% Hispanic). About half (52.9%) have single ventricle physiology and 26% have HF. In a pilot ES cohort of 48 patients, there was an average of 524.2 variants/patient in cardiomyopathy genes of interest. After filtering out common and tolerated variants, 8 loss-of-function and 28 missense variants were identified and interpreted using ACMG criteria. Likely pathogenic or pathogenic (LPP) variants were found in 26.9% (7/26) of HF patients and 9.1% (2/22) of non-HF patients ( p =0.15). The RR for having a cardiomyopathy-associated LPP variant and developing HF in the setting of CHD was 1.60 (95% CI 1.0-2.57). Conclusions: We have established NC-DEFINE, a novel prospectively enrolled CHD cohort, to define the genetic architecture of HF in CHD. In a pilot ES cohort, we found enrichment of rare, LPP variants in cardiomyopathy-associated genes in patients with HF.