Deletion Is Associated With Sex-dependent Cardiomyopathy and Cardiac Mortality: A Translational, Multi-Institutional Cohort Study.

Background: 1p36 deletion syndrome can predispose to pediatric-onset cardiomyopathy. Deletion breakpoints are variable and may delete the transcription factor . Early studies suggest that deletion of may underlie cardiomyopathy in patients with 1p36 deletion; however, the prognostic impact of loss is unknown.

Methods: This retrospective cohort included subjects with 1p36 deletion syndrome from 4 hospitals. Prevalence of cardiomyopathy and freedom from death, cardiac transplantation, or ventricular assist device were analyzed. A systematic review cohort was derived for further analysis. A cardiac-specific knockout mouse ( conditional knockout) was generated. Echocardiography was performed at 4 and 6 to 7 months. Histology staining and qPCR were performed at 7 months to assess fibrosis.

Results: The retrospective cohort included 71 patients. Among individuals with deleted, 34.5% developed cardiomyopathy versus 7.7% of individuals with not deleted (=0.1). In the combined retrospective and systematic review cohort (n=134), deletion-associated cardiomyopathy risk was recapitulated and significant (29.1% versus 10.8%, =0.03). deletion was associated with increased risk of death, cardiac transplant, or ventricular assist device (=0.04). Among those deleted, 34.5% of females developed cardiomyopathy versus 16.7% of their male counterparts (=0.2). We find sex-specific differences in the incidence and the severity of contractile dysfunction and fibrosis in female conditional knockout mice. Further, female conditional knockout mice demonstrate significantly elevated risk of mortality (=0.0003).

Conclusions: deletion is associated with a significantly increased risk of cardiomyopathy and cardiac mortality. conditional knockout mice develop cardiomyopathy in a sex-biased way. Patients with deletion should be assessed for cardiac disease.