P2A053: Prevalence and Clinical Course of Pediatric-onset Arrhythmogenic Cardiomyopathy

Background: Arrhythmogenic cardiomyopathy (ACM) is a heterogenous disorder characterized by myocardial fibrofatty replacement and accompanying arrhythmias. Although typically an adult-onset disorder, clinically manifest ACM occurs in pediatric patients. We aim to determine the prevalence, clinical course, and potential genotype-phenotype correlations associated with pediatric-onset ACM.

Methods: The Mayo Clinic Genetic ACM Registry (N=317) was used to identify all patients < 18 years of age (probands and relatives) at time of clinical presentation and a pathogenic/likely pathogenic (P/LP) variant in ≥ 1 of 9 strong/definitive evidence ACM genes. Ventricular arrhythmia (VA) events were defined as sustained VAs, appropriate implantable cardioverter defibrillator shocks, and sudden cardiac death. Advanced heart failure (AHF) events were defined as ventricular assist device placement or cardiac transplantation. Penetrance was defined as having clinical symptoms or meeting task force criteria for ACM based on echocardiographic and/or imaging evidence.

Results: Overall, 63/317 (20%; 46% female; average age of 11 ± 5 years) ACM patients came to clinical attention prior to the age of 18. Of these, 28/63 (44%; 36% female; mean age at presentation 15 ± 6 years) displayed electrocardiographic and/or imaging evidence of ACM. Among pediatric ACM patients with clinically manifest disease, 12/28 (44%; 47% female; average age 14 ± 6 years) experienced either a VA (n=6; 3 PKP2, 2 LMNA and 1 DSP) or AHF event (n=5; 2 PKP2, 1 LMNA and 2 DSP) with 3 pediatric ACM patients experiencing both VA and AHF events. Interestingly, P/LP variants in DSG2 (1/1; 100%), RBM20 (8/10; 80%), DES (2/3; 67%), PKP2 (7/12; 58%), and DSP (5/11; 45%) demonstrated reasonable penetrance within this pediatric ACM population. However, P/LP variants in LMNA (5/15; 33%) were minimally penetrant and no clinical phenotype was observed in pediatric patients with P/LP variants in DSC2, FLNC, and PLN.

Conclusion: Collectively, close to half of the pediatric patients with a P/LP variant in an ACM-susceptibility gene displayed clinical evidence of ACM during childhood. Furthermore, pediatric-onset ACM is associated with a high rate of VA and AHF events (18% of all pediatric ACM patients and 40% of those with electrocardiographic and/or imaging evidence of ACM). Penetrance in this single-center ACM cohort was highly genotype-specific with DSG2, RBM20, DES and PKP2 and rarely in patients with DSC2, FLNC, or PLN.