Malformations of the human cerebral cortex can lead to clinically important birth defects, resulting in mental retardation, epilepsy, and/or cerebral palsy. Cortical malformations can range anywhere from grossly visible derangements of the cerebral hemispheres, to subtle, focal defects of cortical architecture. Consequently, the wide range of phenotypes includes profoundly crippled children, adults with normal intelligence who present with mild epilepsy, and individuals with no overt symptoms at all. It is increasingly clear that many malformations of the human cortex result from the action of defective genes. We propose to map and clone genes for several autosomal recessive disorders of human cerebral cortical development that are associated with abnormal neuronal migration. Although recessively inherited human cortical malformations are clinically and genetically heterogeneous, our preliminary data suggest that they can be divided into less heterogeneous categories by careful pedigree ascertainment. Through collaborations with clinicians, pedigrees with recessive cortical malformations will be ascertained and studied by performing medical review and MRI brain imaging. Attention will particularly focus on pedigrees that show consanguinity because of the power of consanguinity for mapping rare recessive disease genes. For well-characterized pedigrees that show evidence for simply inherited, highly penetrant recessive traits, DNA samples will be collected and subjected to genome-wide screens to find areas of genetic linkage. Linkage will be tested with standard statistical methods, and multiple distinct pedigrees with the same disorder from genetically isolated populations will be analyzed because of the likelihood of founder mutations that allow for fine genetic mapping and eventually gene identification. Identifying the genes that cause recessive neuronal migration disorders of the cerebral cortex would be important for understanding normal human brain development and evolution, as well as epilepsy pathogenesis.
