CCM2 deletions are a common cause of cerebral cavernous malformations. D.A. Marchuk¹, C.L. Liquori¹, M.J. Berg², F. Squitieri³, T.P. Leedom¹, L. Ptacek⁴, E.W. Johnson⁵. 1) Mol Genet & Microbiol, Duke Univ Medical Ctr, Durham, NC; 2) Strong Epilepsy Center, Dept of Neurology, Univ of Rochester Medical Ctr, Rochester, NY; 3) Neurogenetics Unit, Istituto di Ricovero e Cura a Carattere Scientifico, Neuromed, Pozzilli, Italy; 4) Dept of Neurology, Univ of California San Francisco, San Francisco, CA; 5) Molec Diagnostics and Biobanking, Prevention Genetics, Marchfield, WI.
   Cerebral cavernous malformations (CCMs) are vascular abnormalities of the brain that can result in a variety of neurological disabilities, including stroke and seizures. Mutations in the gene Krit1 are responsible for CCM1, mutations in the gene MGC4607 are responsible for CCM2, and mutations in the gene PDCD10 are responsible for CCM3. Over several years, we have collected 64 CCM probands with family history and/or multiple lesions, and sequence analysis showed that a high proportion (41%) of these probands lacked any identifiable mutation. We now report that large genomic CCM2 deletions represent a major component of this disease which are missed by routine mutation screens. We used multiplex ligation-dependent probe analysis (MLPA) to screen 26 non-CCM1, non-CCM2, and non-CCM3 probands for potential deletions or duplications within all three CCM genes. We identified a total of 14 deletions - 1 in the CCM1 gene, 13 in the CCM2 gene, and none in the CCM3 gene. Interestingly, 50% of the identified CCM2 deletions span exons 2-10. Sequence and deletion analysis of our 64 probands gave a frequency ratio of 39% (25/64) CCM1, 36% (23/64) CCM2, 6% (4/64) CCM3, and 19% (12/64) unknown. These data indicate that the prevalence of CCM2 is much higher than previously suspected and that the frequency of CCM1 mutations and CCM2 mutations are approximately equal. With respect to CCM2, we highly recommend that deletion screening should be performed to avoid missing over half of the responsible mutations. The fact that 19% of CCM mutations still remain unidentified suggests either that the remaining mutations cannot be identified by sequence or deletion analysis or that there may be an additional CCM gene(s).