P194: Advancing diagnostic precision in rare genetic disorders: Insights from the University of Wisconsin Undiagnosed Disease Program

Introduction: Cardiomyopathies (CM) are a leading cause of heart failure.Identification of genetic risk preemptively may allow detection of the earliest phenotypic manifestations through implementation of interval-based cardiac screening.Previous population-based genetic screening studies have inadequate phenotyping and limited follow-up.Methods: We analyzed 52,863 patients from a quaternary medical center-based biobank cohort for reportable variants in 22-cardiomyopathy genes.Prioritization of genetic variants was performed using Semi-Automated Variant Interpretation, a novel software that has been previously developed and validated at our center.Prioritized variants were then manually curated by at least 2 independent variant interpretation specialists.Clinical phenotypes and outcomes of participants with likely pathogenic/pathogenic (LP/P) variants were determined.Results: LP/P cardiomyopathy variants were present in ~1% of our cohort (n=427) within the following genes: BAG3 (n=3), DES (n=1), DSG2 (n=4), DSP (n=36), FLNC (n=20), LMNA (n=9), MYBPC3 (n=123), MYH7 (n=67), MYL2 (n=2), MYL3 (n=1), PKP2 (n=45), RBM20 (n=1), TNNC1 (n=1), TNNI3 (n=18), TNNT2 (n=5), TPM1 (n=3), TTN (n=101).A definitive disease penetrance defined as heart failure or cardiomyopathy was found in 34% (n=145) of genotype positive (G+) individuals.Possible disease penetrance defined as presence of structural heart disease identified by echocardiography was found in an additional 16% (n=68) of participants (eg, concentric left ventricular hypertrophy, diastolic dysfunction, biatrial or left/right atrial enlargement).Combined definitive and possible disease penetrance was found in 50% (n=213) of G+ individuals.Arrhythmias and/or cardiac conduction disease (eg, atrial fibrillation, atrioventricular block, ventricular arrhythmia) were present in 41% (n=176) of G+ individuals.Conclusion: Cardiomyopathy associated LP/P variants are present in a small subset of a large quaternary medical center population as previously reported but unlike prior studies, disease penetrance manifesting as cardiac structural abnormalities and heart failure is high in G+ individuals.