Over the past half century molecular biology has led to great advances in our understanding of angio- and vasculogenesis and in the treatment of malformations resulting from these processes gone awry. Given their sporadic and familial distribution, their developmental and pathological link to capillary telangiectasias, and their observed chromosomal abnormalities, cerebral cavernous malformations (CCMs) are regarded as akin to cancerous growths. Although the exact pathological mechanisms involved in the formation of CCMs are still not well understood, the identification of 3 genetic loci has begun to shed light on key developmental pathways involved in CCM pathogenesis. Cavernous malformations can occur sporadically or in an autosomal dominant fashion. Familial forms of CCMs have been attributed to mutations at 3 different loci implicated in regulating important processes such as proliferation and differentiation of angiogenic precursors and members of the apoptotic machinery. These processes are important for the generation, maintenance, and pruning of every vessel in the body. In this review the authors highlight the latest discoveries pertaining to the molecular genetics of CCMs, highlighting potential new therapeutic targets for the treatment of these lesions.

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Cerebral cavernous malformations (CCMs) are vascular lesions that afflict the central nervous system. The prevalence of CCMs in the general population is 0.1–0.5%, and the disease may present as a sporadic or familial form. The familial form of the disease shows a strong predilection for the Hispanic–American ethnic group. Current research suggests that the familial form of CCMs arises due to mutations that occur in one or more of three genes: CCM1 , CCM2 and CCM3 , which encode KRIT‐1 protein, malcavernin and programmed cell death 10, respectively. This article examines the known genetic insults to the CCM genes that may cause mutated, nonfunctioning protein products. Each has unique downstream intracellular effects that lead to CCM formation. Recommendations regarding genetic counselling for families with CCMs are presented. Key Concepts: Genetic Counselling, gross pathology and molecular genetics of CCM, differences in inheritance patterns between familial and sporadic CCM. CCMs are mulberry‐like vascular defects characterized by enlarged, leaky capillaries within the central nervous system. CCMs have a strong predilection for the Hispanic‐American ethnic group and may be present in patients as either a sporadic single lesion or an inherited multi‐lesion form. The most common symptoms for CCM patients with supratentorial vascular lesions are recurrent headaches and seizures whereas infratentorial lesions result in focal neurological defects and ataxia. The familial form of CCM disease is caused by mutations in one or more of the three genes: CCM1 , CCM2 and CCM3 whose protein products are relevant to endothelial proliferation regulation, intracellular osmoregulation and endothelial migration, respectively. K‐Rev interaction trapped 1, the protein product of CCM1 , is mutated in 56% of the familial CCM patients thus preventing its association with malcavernin and RAP‐1A/ICAP1 α leading to abnormal vascular morphogenesis and dysregulation of sprouting angiogenesis For the familial variant of CCMs, the strong genetic inheritance patterns suggest physicians should recommend patients for genetic screening for CCM1 , CCM2 and CCM3 mutations, as well as for patients with solitary lesions and a family history of the disease.