The genetic forms of cerebral cavernomatosis (CCM) are autosomal dominant. Three CCM genes have been identified: KRIT1/CCM1 and MGC4607/CCM2, both located on chromosome 7 and PDCD10/CCM3 located on chromosome 3. The vast majority of patients with a genetic form of the disease have multiple lesions that can be detected on a cerebral MRI. A patient with only one lesion on an MRI that includes a gradient-echo sequence is, in most cases, suffering from a non-genetic form of the disease. In patients with a single gradient-echo lesion, molecular testing is not indicated. In certain cases, however, the mutation appears de novo in a patient although neither of the parents is a carrier. These are sporadic but genetic forms of the disease with the same risk of transmission to children as the risk in a patient with the familial form of the disease.
In approximately 50% of cases, the mutation is located in the CCM1 gene. In 15% of cases, the mutation is located in the CCM2 gene and, in 10% of cases, the mutation is located in the CCM3 gene. It is important to note that, in some 25% of patients, the screening of these 3 genes does not reveal any mutation yet there is a very high probability that these forms "with no identified mutation" are genetic forms which could be explained by the possible non-proven existence of other CCM genes that have not yet been identified and/or the existence of mutations that cannot be detected by screening the coding areas of one of the 3 known CCM genes and/or the possibility of mosaics.
In most cases, the identified mutations lead to the appearance of a premature stop codon or the partial or complete deletion of one of the 3 CCM genes. Because of this, it is very easy to interpret the test results.
To meet demand from clinicians confronted with atypical forms of cavernomatoses and demands for genetic counselling in sporadic forms with multiple lesions, our laboratory has introduced routine comprehensive sequencing of the 3 genes (KRIT1, MGC4607 and PDCD10), testing of the cDNA of these 3 genes obtained from peripheral leukocytes and a QMPSF approach to the search for gene deletion. The test is estimated to have approximately 75% sensitivity (cf. above).
For asymptomatic patients, no screening is carried out until they reach the age of 18.