Here we report a 10-year-old girl diagnosed with dilated cardiomyopathy, decompensated heart failure, and evidence of global end-organ hypoperfusion in the setting of severely depressed biventricular systolic function. Exome sequencing revealed a novel germline heterozygous frameshift variant resulting from a 2-bp deletion, c.1496_1497del (p.Pro499Leufs∗104) in the PR-domain containing 16 (PRDM16) gene, functionally proven to result in PRDM16 deficiency, evidenced by pretermination of PRDM16 protein. Furthermore, the consistent presence of the PRDM16 variant in affected family members, and its absence in non-affected family members, combined with a strong maternal family history of cardiomyopathy, provides compelling support for the pathogenicity of the PRDM16 variant. Nevertheless, there is no obvious sex bias in our reported family in terms of PRDM16-related cardiomyopathy. We showed that this variant led to impaired mitochondrial function and ATP production. Based upon the collective results of functional studies, clinical features, and family history, this novel heterozygous frameshift germline variant in PRDM16 was determined to be the cause of the familial cardiomyopathy and heart failure. This novel pathogenic PRDM16 variant has potential utility in diagnosis and prognosis and underscores the critical and unique role of PRDM16 in human cardiomyopathy.