Abstract 4145605: Disease-Causing Variants in Genes Associated with RASopathy and Aortopathy in Advanced Dilated Cardiomyopathy

Introduction: Genetic testing reveals the presence of disease-causing (American College of Genetics and Genomics [ACMG] likely pathogenic [LP] or pathogenic [P]) variants in about 20% of patients with dilated cardiomyopathy (DCM). Exome sequencing can identify variants in novel genes that may be associated with DCM. Research Question: Do patients with advanced DCM harbor LP/P variants in genes associated with non-dilated cardiac, muscular, or vascular phenotypes? Goals: We determined the prevalence of LP/P variants in genes associated with 3 non-dilated cardiac, 1 muscular, and 1 vascular phenotype in 60 patients with advanced DCM requiring heart transplant. Methods: We conducted a retrospective study of patients who received a heart transplant between 2017 and 2023 at Cedars Sinai and who provided informed consent to participate. All subjects had DCM defined by LVEF ≤ 50% and LVEDD ≥ 95 th percentile for sex and height. Whole exome sequencing was performed on explanted heart tissue. We assessed for rare variants in genes classified as having definite, strong, or moderate association with DCM, hypertrophic cardiomyopathy (HCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), RASopathy, muscular dystrophy (MD), and thoracic aortic aneurysm (TAA) by ClinGen Gene-Disease Validity Curation Expert Panels. Variant pathogenicity was determined using ACMG criteria. Results: We identified 13 patients (22%) with LP/P variants in DCM genes. For non-DCM genes, we identified 12 LP/P variants in a total of 11 patients (18%) (FIGURE). There were no variants in HCM or ARVC genes. We identified 5 patients each with 1 LP/P variant in RASopathy genes; of these, 2 were in conjunction with DCM variants. We identified 2 patients each with 1 LP/P variant in MD genes. We identified 5 patients with LP/P variants in TAA genes; of these, 2 were in conjunction with a single DCM variant. No patients carrying RASopathy, MD, or TAA LP/P variants exhibited non-cardiac phenotypic manifestations of these conditions. Conclusion: In patients with advanced DCM requiring heart transplant, we found that 18% of patients harbored LP/P variants in genes associated with RASopathy, MD, or TAA, without exhibiting non-cardiac phenotypic manifestations of these conditions. Further research is needed to validate these gene variants as primary or secondary causes of DCM. If validated, more expansive genetic testing may be indicated in patients with advanced DCM.