Genetics of cerebral cavernous malformations: current status and future prospects

Cerebral cavernous malformations (CCM) are vascular lesions which affect up to 0.5% of the general population, predisposing to headaches, seizures, cerebral hemorrhages and focal neurological deficits. CCM occurs in both sporadic and familial forms; familial cases follow an autosomal-dominant mode of inheritance and are caused by mutations in CCM1 (KRIT1), CCM2 (MGC4607), or CCM3 (PDCD10). Somatic mutations within the three CCM genes have been identified in CCM lesions from both sporadic and familial patients. We reviewed articles published in PubMed in English prior to March 2015 and provide an update on CCM mutations and the screening strategies used to identify them. Further, we summarize the specific clinical features related to CCM genotypes. As 5% to 15% of familial CCM cases remain genetically unexplained, we also discuss future approaches to expand understanding of the genetic architecture of CCM. Finally, we discuss possible genetic modifiers of CCM disease severity and progression. Understanding the genetic architecture of CCM is essential for an earlier diagnosis of the disease, predictive testing of at-risk patients, and design of targeted medical therapies of which there are currently none available.