The indel variant in JAM3 was identified in the binding site of transcription factor EZH2 which controls the methylation of H3K27 histone and can also act through methylation of nonhistone proteins, being a potential mechanism for EZH2-mediated gene activation, the perturbation of this pathway can lead to cardiac defects and was already established as a driven mechanism in some types of cancer [53–55]. The gene discussed is EZH2; the disease is cancer.