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Genetic Heterogeneity of Inherited Cerebral Cavernous Malformation

Günel, Murat M.D.; Awad, Issam A. M.D.; Finberg, Karin B.S.; Steinberg, Gary K. M.D., Ph.D.; Craig, Holly Duncan M.Phil.; Cepeda, Obed B.S.; Nelson-Williams, Carol B.S.; Lifton, Richard P. M.D., Ph.D.

Rapid Communication

Objective: Cerebral cavernous malformation (CCM) is frequently an inherited disorder showing autosomal dominant transmission. Genetic analysis has localized a gene causing CCM to a segment of the long arm of human chromosome 7 (7q). This evidence derives from investigation of a small 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.

Methods: We have studied subjects from two non-Hispanic families with inherited CCM. The clinical features of CCM in these families are indistinguishable 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 mutation on 7q, we compared the inheritance of CCM to the inheritance of genetic markers on 7q.

Results: Genetic analysis demonstrates independent 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 these 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: These findings demonstrate that inherited CCM is not always caused by a mutant gene on 7q, indicating the presence of at least a second gene in which mutation can cause CCM. These results have implications for genetic testing and the pathogenesis of this disorder.

Howard Hughes Medical Institute and Boyer Center for Molecular Medicine(MG, KF, HDC, OC, CN-W, RPL), Section of Neurosurgery (MG, IAA), Department of Cell Biology (MG), Departments of Medicine and Genetics (RPL), Yale University School of Medicine, New Haven, Connecticut; Department of Neurosurgery (GKS), Stanford University School of Medicine, Palo Alto, California

Received, January 11, 1996. Accepted, March 13, 1996.

Reprint requests: Richard P. Lifton, M.D., Ph.D., Howard Hughes Medical Institute, Boyer Center for Molecular Medicine, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06510.

Copyright © by the Congress of Neurological Surgeons