Familial Stroke Studies

Pedigree of a family with stroke inherited as an autosomal dominant disorder.

Pedigree of a family with stroke inherited as an autosomal dominant disorder.

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 Notch 3 gene [OMIM*600276] were observed to result in CADASIL. Three genes have been identified to produce hemorrhagic stroke due to cerebral cavernous malformation (CCM). This CCM causes vascular capillary abnormalities that easily rupture. Micro–tubule–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 to cause CCM. The third gene is the programmed cell death gene 10 [OMIM*609118]. This project seeks to develop a Mayo Clinic Jacksonville molecular genetics familial stroke program. The hypothesis is that the identification of kindreds who have a family history of stroke will through classical linkage studies identify new genes that when mutated effect a stroke phenotype. Through ongoing clinical stroke research by Dr. Meschia we have identified 275 probands who have already donated DNA in a case–control study that report a family history of stroke. These probands will be screened for known variants associated with stroke. The families will then be expanded to include other affected and unaffected members.