Different spectra of genomic deletions within the CCM genes between Italian and American CCM patient cohorts.

Cerebral cavernous malformations (CCMs) are vascular abnormalities of the brain that can result in hemorrhagic stroke and seizures. Familial forms of CCM are inherited in an autosomal-dominant fashion, and three CCM genes have been identified. We recently determined that large genomic deletions in the CCM2 gene represent 22% of mutations in a large CCM cohort from the USA. In particular, a 77.6 kb deletion spanning CCM2 exons 2-10 displays an identical recombination event in eight CCM probands/families and appears to be common in the US population. In the current study, we report the identification of six additional probands/families from the USA with this same large deletion. Haplotype analysis strongly suggests that this common deletion derives from an ancestral founder. We also examined an Italian CCM cohort consisting of 24 probands/families who tested negative for mutations in the CCM1, CCM2, and CCM3 genes by DNA sequence analysis. Surprisingly, the common CCM2 deletion spanning exons 2-10 is not present in this population. Further analysis of the Italian cohort by multiplex ligation-dependent probe analysis identified a total of ten deletions and one duplication. The overall spectrum of genomic rearrangements in the Italian cohort is thus quite different than that seen in a US cohort. These results suggest that there are elements within all three of the CCM genes that predispose them to large deletion/duplication events but that the common deletion spanning CCM2 exons 2-10 appears to be specific to the US population due to a founder effect.