Familial CCM lesions form as a consequence of mosaic complete inactivation of CCM1, -2, or -3. Here, we have used Cas9-CRISPR mutagenesis to create such a mosaicism for ccm2 in zebrafish and show that surviving adult ccm2 CRISPR animals develop brain and extracranial lesions that closely resemble those observed in humans with CCM. This evidence concerns the gene KRIT1 and cerebral cavernous malformation.