In summary, our exome findings of the heterozygous loss-of-function PRDM16 variant (p.Pro499Leufs∗104) combined with the inheritance, extensive family history of cardiac failure, and functional defects in mitochondria after PRDM16 deletion, provide evidence that PRDM16 loss of function causes cardiomyopathy and heart failure with variable presentations and ages of onset. The gene discussed is PRDM16; the disease is heart failure.