Hypertrophic cardiomyopathy (HCM) is a cardiovascular disease with high heterogeneity. Limited knowledge concerning the genetic background of nearly 40% HCM cases indicates there is a clear need for further investigation to explore the genetic pathogenesis of the disease. In this study, we undertook a whole exome sequencing (WES) approach to identify novel candidate genes and mutations associated with HCM. The cohort consisted of 74 unrelated patients with sporadic HCM (sHCM) previously determined to be negative for mutations in eight sarcomere genes. The results showed that 7 of 74 patients (9.5%) had damaging mutations in 43 known HCM disease genes. Furthermore, after analysis combining the Transmission and De novo Association (TADA) program and the ToppGene program, 10 putative genes gained priority. A thorough review of public databases and related literature revealed that there is strong supporting evidence for most of the genes playing roles in various aspects of heart development. Findings from recent studies suggest that the putative and known disease genes converge on three functional pathways: sarcomere function, calcium signaling and metabolism pathway. This study illustrates the benefit of WES, in combination with rare variant analysis tools, in providing valuable insight into the genetic etiology of a heterogeneous sporadic disease.