Familial Stroke Studies

The most successful approach to the mapping of stroke-related genes has been the identification of rare Mendelian forms. The classical linkage method employing large familial aggregates that display patterns of stroke inheritance (dominant/recessive) has identified genes involved in monogenic forms of disease. Cerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL) is a rare form of small-vessel occlusive disease.

Pathogenic mutations in the NOTCH3 gene (OMIM*600276) were observed to result in CADASIL. Three genes have been identified to produce hemorrhagic stroke because of cerebral cavernous malformation. Cerebral cavernous malformation causes vascular capillary abnormalities that easily rupture. Microtubule-associated protein krev interaction trapped 1 (KRIT1; OMIM*604214) was found to harbor rare familial mutations. Subsequently, a novel gene (MGC4607 [OMIM*607929]) similar to ICAP1α, a KRIT1 binding partner, was identified as causing cerebral cavernous malformation. The third gene is the programmed cell death gene 10 (OMIM*609118).

Through this project, our lab seeks to develop a molecular genetics familial stroke program at Mayo Clinic in Jacksonville, Florida. Our hypothesis is that the identification of kindreds who have a family history of stroke will through classical linkage studies lead to identification of new genes that when mutated effect a stroke phenotype.

Through ongoing clinical stroke research by Mayo Clinic neurologist James F. Meschia, M.D., our lab has identified 275 probands who have already donated DNA in a case-control study that report a family history of stroke. These probands are being screened for known variants associated with stroke, and other affected and unaffected members are being included.