Cerebral Cavernous Malformations via the KRIT1/CCM1 Gene, Exon 10

Cerebral cavernous malformations (CCMs) are congenital vascular anomalies of the brain that can cause significant neurological disabilities, including intractable seizures and hemorrhagic stroke. CCMs represent 5-15% of all cerebral vascular malformations and occur in ~0.5% of the general population. CCMs have been reported in infants and children, but the majority of patients present with symptoms between the second and fifth decades. CCMs occur in a sporadic form in which patients usually present with a single lesion and no family history or a familial form characterized by multiple lesions and usually a strong family history. A significant fraction of “sporadic” cases with multiple lesions are members of an undiagnosed affected family. Not all patients with CCMs are clinically symptomatic. Symptomatic lesions may often be removed surgically. For additional information, see Zabramski et al. J Neurosurg 80: 422-432, 1994, Morrison and Akers 2011 GeneReviews (http://www.geneclinics.org/), and Angioma Alliance (http://www.angiomaalliance.org/).

Familial cerebral cavernous malformations (CCMs) show autosomal dominant inheritance. Three causative genes for CCMs have been identified: KRIT1 (also called CCM1), encoding a protein that interacts with the Krev-1/rap1a tumor suppressor; CCM2, which is similar to the KRIT1 binding partner ICAP1α; and PDCD10 (or CCM3), the programmed cell death 10 gene. Almost all causative variants (in all three genes) are either nonsense, frameshift, splicing or deletion; missense variants are rare or absent (Denier et al. Ann Neurol 60:550-556, 2006; Plummer et al. Curr Neurol Neurosci Rep 5:391-396, 2005 ; Liquori et al. Am J Hum Genet 80:69-75, 2007). Large, pathogenic deletions in the three CCM genes are relatively common (Liquori et al. 2007; Felbor et al. Neurogenetics 8:149-153, 2007). Penetrance of pathogenic variants in the three CCM genes is incomplete (Morrison and Akers. GeneReviews. 2011). CCMs appear to occur only when there has been a "second hit" somatic variant in the normal allele in an endothelial cell (Akers et al. Hum Mol Genet 18:919-930, 2009; Pagenstecher et al. Hum Mol Genet 18:911-918, 2009).

The identification of the familial Hispanic KRIT1/CCM1 variant entails bidirectional DNA sequencing of the full coding region of KRIT1 exon 10. This test should be ordered first if the patient has Hispanic ancestry. PreventionGenetics also offers sequencing tests for the full KRIT1, CCM2, and PDCD10 genes (Tests #120-123) , a PCR test for the most common CCM2 gene deletion (Test #124), and an aCGH test for all larger copy number variants in the three CCM genes (Test #600).