Background MYBPC 3 dysfunctions have been proven to induce dilated cardiomyopathy, hypertrophic cardiomyopathy, and/or left ventricular noncompaction; however, the genotype–phenotype correlation between MYBPC 3 and restrictive cardiomyopathy ( RCM ) has not been established. The newly developed next‐generation sequencing method is capable of broad genomic DNA sequencing with high throughput and can help explore novel correlations between genetic variants and cardiomyopathies. Methods and Results A proband from a multigenerational family with 3 live patients and 1 unrelated patient with clinical diagnoses of RCM underwent a next‐generation sequencing workflow based on a custom AmpliSeq panel, including 64 candidate pathogenic genes for cardiomyopathies, on the Ion Personal Genome Machine high‐throughput sequencing benchtop instrument. The selected panel contained a total of 64 genes that were reportedly associated with inherited cardiomyopathies. All patients fulfilled strict criteria for RCM with clinical characteristics, echocardiography, and/or cardiac magnetic resonance findings. The multigenerational family with 3 adult RCM patients carried an identical nonsense MYBPC 3 mutation, and the unrelated patient carried a missense mutation in the MYBPC 3 gene. All of these results were confirmed by the Sanger sequencing method. Conclusions This study demonstrated that MYBPC 3 gene mutations, revealed by next‐generation sequencing, were associated with familial and sporadic RCM patients. It is suggested that the next‐generation sequencing platform with a selected panel provides a highly efficient approach for molecular diagnosis of hereditary and idiopathic RCM and helps build new genotype–phenotype correlations.