GENETIC-HETEROGENEITY OF INHERITED CEREBRAL CAVERNOUS MALFORMATION

Objective: Cerebral cavernous malformation (CCM) is frequently an inhe rited disorder showing autosomal dominant transmission. Genetic analys is has localized a gene causing CCM to a segment of the long arm of hu man chromosome 7 (7q). This evidence derives from investigation of a s mall number of families, mostly of Hispanic American descent. In this study, we have tested whether inherited CCM is always due to mutation in this 7q gene, or whether mutations in other genes can cause CCM. Me thods: We have studied subjects from two non-Hispanic families with in herited CCM. The clinical features of CCM in these families are indist inguishable from those in kindreds in which CCM is due to mutation in the 7q gene. To test whether CCM in these kindreds is caused by a muta tion on 7q, we compared the inheritance of CCM to the inheritance of g enetic markers on 7q. Results: Genetic analysis demonstrates independe nt inheritance of CCM and markers on 7q in both families studied. This evidence excludes mutation in the 7q gene as the cause of CCM in thes e families, with odds against CCM being due to mutation in 7q in each family of more than 100,000:1 and 100:1, respectively.Conclusion: Thes e findings demonstrate that inherited CCM is not always caused by a mu tant gene on 7q, indicating the presence of at least a second gene in which mutation can cause CCM. These results have implications for gene tic testing and the pathogenesis of this disorder.