A FOUNDER MUTATION AS A CAUSE OF CEREBRAL CAVERNOUS MALFORMATION IN HISPANIC AMERICANS

Background. Cerebral cavernous malformation is a vascular disease of t he brain causing headaches, seizures, and cerebral hemorrhage. Familia l and sporadic cases are recognized, and a gene causing familial disea se has been mapped to chromosome 7. Hispanic Americans have a higher p revalence of cavernous malformation than do other ethnic groups, raisi ng the possibility that affected persons in this population have inher ited the same mutation from a common ancestor. Methods. We compared th e segregation of genetic markers and clinical cases of cavernous malfo rmation in Hispanic-American kindreds with familial disease; we also c ompared the alleles for markers linked to cavernous malformation in pa tients with familial and sporadic cases. Results. All kindreds with fa milial disease showed linkage of cavernous malformation to a short seg ment of chromosome 7 (odds supporting linkage, 4x10(10):1), Forty-seve n affected members of 14 kindreds shared identical alleles for up to 1 5 markers linked to the cavernous-malformation gene, demonstrating tha t they had inherited the same mutation from a common ancestor. Ten pat ients with sporadic cases also shared these same alleles, indicating t hat they too had inherited the same mutation. Thirty-three asymptomati c carriers of the disease gene were identified, demonstrating the vari ability and age dependence of the development of symptoms and explaini ng the appearance of apparently sporadic cases. Conclusions. Virtually all cases of familial and sporadic cavernous malformation among Hispa nic Americans of Mexican descent are due to the inheritance of the sam e mutation from a common ancestor. (C) 1996, Massachusetts Medical Soc iety.