Abstract 15579: Stem Cell Modeling of a Candidate Genetic Variant in a Family With Complex Inherited Cardiomyopathy

Introduction: Inherited cardiomyopathies, such as arrhythmogenic right (or left) ventricular cardiomyopathy (ARVC; ALVC) and dilated cardiomyopathy (DCM), can lead to sudden cardiac death. Mechanisms of arrhythmogenesis in these cardiomyopathies are not fully understood, with ~ 20% of patients carrying a pathogenic variant in a validated cardiomyopathy-associated gene.

Aims: Here, we investigate a family with highly variable expression of arrhythmogenic cardiomyopathy. The two affected siblings have differential ventricle involved and arrhythmia burden: with one fulfilling criteria for ARVC, and the other for ALVC. Their father has a non-ischemic cardiomyopathy with ventricular arrhythmias and a family history of sudden death. The maternal side is unaffected. The sibling with ALVC harbors a paternally inherited rare missense variant of uncertain significance (VUS) in plakoglobin ( JUP) (c.356C>T; p.Pro119Leu), an ARVC-associated gene that does not segregate in the sibling with ARVC.

Hypothesis: Study of patient-specific inducible pluripotent stem cell-derived cardiomyocytes (iPSC-CM) can define an elusive genetic etiology as well molecular pathways associated with cardiomyopathy in the affected family members.

Methods: We reprogrammed iPSC lines from 3 affected family members and 2 unaffected maternal controls and differentiated them into cardiomyocytes.

Results: Differentiation to iPSC-CMs resulted in transcriptionally upregulated markers of cardiac stress and contractile function in affected family members ( NPPA, NPPB, MYH7 ). iPSC-CM harboring JUP c.356C>T did not differ in plakoglobin RNA or protein expression. Hypertrophy was observed in the iPSC-CMs from affected family members after isoproterenol stimulation. Whole exome sequencing results revealed rare candidate variants (MAF<5x10 ^-5 , REVEL>0.7) that segregated in affected family members.

Conclusions: iPSC-CMs from affected family members recapitulate cardiomyopathy phenotypes. Affected family members harbor novel candidate variants not previously associated with cardiomyopathies. Future work will utilize base editing to evaluate for compound contributions of several novel VUS on cardiomyopathy phenotypes in iPSC-CM from family members.