LINKAGE OF THE LOCUS FOR CEREBRAL CAVERNOUS HEMANGIOMAS TO HUMAN-CHROMOSOME-7Q IN 4 FAMILIES OF MEXICAN-AMERICAN DESCENT

Objective: To determine with greater precision the map location of the locus associated with familial cavernous hemangiomas. Background: Cav ernous malformations of the brain are a significant cause of seizures, progressive or apoplectic neurologic deficit, and headache. Prevalenc e estimates from autopsy series vary from 0.39 to 0.9%. This disorder (OMIM #116860) can be inherited as an autosomal dominant trait with va riable penetrance, Linkage to markers on the long arm of chromosome 7 was recently reported in separate reports in three apparently unrelate d Hispanic kindreds as well as in two kindreds of non-Hispanic descent , Design/Methods: We examined clinically, by MRI scanning, and by path ologic examination of surgical specimens, members of four large Mexica n-American families segregating cavernous hemangiomas of the brain. Li nkage analysis was performed with use of blood specimens from morpholo gically proven cases, Two-point linkage analysis was performed with th e MLINK program of the LINKAGE package, Multipoint analysis was perfor med between two markers and the disease locus with LINKMAP in the FAST LINKAGE package. Allele frequencies were set as described by the Genom e Database (GDB). Maximum penetrance for the disease allele was set to 0.75. Results: The highest lod score was observed for marker D7S652 w ith Z(max) = 6.66 at theta(max) = 0.00. Multipoint LOD score analysis placed the disease locus in the 11 cM interval between markers D7S630 and D7S527 with Z(max) = 9.19. Haplotype analysis is in agreement with the placement of the disease gene between D7S630 and D7S527 and furth er shows a minimal shared region within this interval, indicating a fo under effect in the establishment of the mutation in these families. C onclusions: We confirmed the linkage of cavernous hemangioma to marker s on the long arm of chromosome 7q, and the estimate of the map locati on has been refined to a region of shared haplotype between markers D7 S630 and D7S527 in four Mexican-American families who may be descended From a common ancestor in Sonora County, Mexico.