Abstract 9544: PRDM16 Loss in 1p36 Deletion Syndrome is Associated With Worse Cardiovascular Outcomes: A Multi-Institutional Registry Study

Abstract

Introduction: 1p36 deletion syndrome can confer a predisposition to pediatric-onset cardiomyopathy. 1p36 deletion breakpoints are variable and can delete PRDM16 , a cardiac transcription factor. Early studies suggest PRDM16 loss may underlie cardiomyopathy in patients with 1p36 deletion; however, the prognostic impact of PRDM16 loss is unknown. Hypothesis: Deletion of PRDM16 in 1p36 deletion syndrome (“ PRDM16 deleted”) is associated with the development of cardiomyopathy and adverse cardiovascular outcomes. Methods: This registry study included Duke University Hospital, Texas Children’s Hospital, Primary Children’s Hospital, & Le Bonheur Children’s Hospital. Standard descriptive statistics and Kaplan-Meier estimates were generated. The composite primary outcome was freedom from death, cardiac transplantation, or ventricular assist device (VAD) implantation. A cardiac-specific conditional Prdm16 knockout mouse ( Prdm16 cKO) was generated. Echocardiography, qPCR, and fibrotic staining were performed at 29 weeks. Results: 66 individuals met the inclusion criteria of 1p36 deletion syndrome and at least one clinical encounter. Among individuals with PRDM16 deleted, 37.9% developed cardiomyopathy versus 4.3% of individuals with PRDM16 not deleted (p=0.09). The most common cardiomyopathies in individuals with PRDM16 deleted were LVNC (27.6%) and DCM (13.8%). Individuals with PRDM16 deleted had a 65% probability of developing systolic dysfunction by age 18. Notably, PRDM16 deletion was associated with a significantly increased risk of death, cardiac transplant, or VAD (p=0.04) versus those with PRDM16 not deleted. Prdm16 cKO mice exhibited an increased risk of mortality (p=0.05) and decreased ejection fraction (p<0.01). Prdm16 cKO mice demonstrated significantly increased cardiac fibrosis (p<0.0001), and Tgf-β and Nppb mRNA were significantly upregulated (p<0.05). Conclusions: PRDM16 deletion as part of 1p36 deletion syndrome confers a significantly increased risk of cardiac mortality. Murine models of cardiomyocyte Prdm16 loss demonstrate an increased risk of mortality and cardiomyopathy development. Patients with 1p36 deletion syndrome should be assessed for cardiac disease, particularly those with PRDM16 deletions.