PO-01-015 YIELD OF GENETIC TESTING AND RESULT UTILITY IN A COHORT OF 2100 DCM PATIENTS

Abstract

Familial dilated cardiomyopathy (DCM) is typically an autosomal dominant (AD), monogenic disorder. Advances in gene-specific precision medicine approaches increasingly highlight the importance of genetic testing for patients with this diagnosis. The yield of genetic testing in DCM has largely been documented by single center studies and have not evaluated the utility of results for gene-specific management purposes. We report the yield of genetic testing in a large cohort of patients with a clinical suspicion of DCM from multiple centers and describe the potential clinical utility of results. This was a retrospective review of consecutive, deidentified patients who underwent genetic testing with a multigene, cardiomyopathy-focused next generation sequencing (NGS) panel. Patients had a confirmed or suspected diagnosis of DCM based on the test requisition received. Panels included sequence and copy number variant (CNV) analysis by NGS of 23 to 316 genes. An informative result was defined as the identification of pathogenic (P) or likely pathogenic (LP) variant(s) using a modified ACMG/AMP classification scheme. A total of 2,100 index patients underwent testing; 56.4% were tested with large panels (101-316 genes; n=1,184). Sequencing and CNV analysis was performed in 73.0% (n=1,533) of patients and panels that included mtDNA were performed for 38.3% (n=804). In this cohort, 24.2% (n=508) of patients received an informative result. AD inheritance was seen in 94.1% (n=478), followed by autosomal recessive (AR) in 2.6% (n=13), X-linked in 2.0%; (n=10) and mitochondrial in 1.4%; (n=7). Thirteen patients (2.6%) had two P/LP variants in AD genes. The most frequent genes were TTN (46.3%), DSP (6.9%), LMNA (6.9%), RBM20 (5.6%) and MYH7 (5.4%). Among patients with informative results, 12.5% (n=64) had a result associated with neuromuscular or metabolic conditions, 17.9% (n=91) had a result associated with ICD recommendations, and 61.8% (n=314) had a result associated with a clinical trial (clinicaltrials.gov). In this cohort, almost 1 in 4 patients received an informative genetic test result. A total of 5.9% of informative results were in genes associated with an inheritance other than AD. In this cohort, 22.3% received an informative result requiring extra-cardiac management, applicable gene-specific management or potential clinical trial eligibility. This work further supports the utility of genetic testing using large multigene panels for DCM.