Project Summary/Abstract: Developmental brain malformations are at the core of significant neurological diseases affecting many families in the United States and around the world. Epilepsy, specific learning deficits and intellectual disabilities, cerebral palsy, and abnormalities of brain size can often be attributed to pathological malformations of the cerebral cortex. Although symptoms such as epilepsy and intellectual disabilities may appear broadly in the population for any number of reasons, our focus on those cases associated with cortical malformations highlights individual developmental pathways likely represented by innumerable and rare Mendelian alleles. Our lab has uncovered dozens of genes associated with these conditions, and we are beginning to dissect the mechanisms underlying early cortical development. However, we know many more genes are yet to be discovered and these currently unidentified genes will provide even more important insight into brain development and function. The goal of our research is to identify novel genetic factors that result in abnormal human cerebral cortical development. This is achieved through 1] ascertaining families with congenital brain malformations, presumably due to inherited factors, and categorizing conditions using neuroimaging data, 2] identifying the genes that harbor mutations that cause the malformations, and 3] describing the function of these genes. We focus on the Middle East for ascertainment of families, where the prevalence of intra-familial marriage and large family size enriches this population for rare Mendelian disorders and offers significant power to study even noncoding mutations, which are typically more difficult to characterize. Causative mutations are identified using whole exome sequencing or whole genome and RNA sequencing when the mutation is not exonic. The mutated gene is further characterized in cell lines, zebrafish, and mouse or ferret models in order to elucidate its function. The discovery of new genes, which when mutated result in abnormal brain development, impacts human health in several ways. These discoveries 1] provide insight into classification and diagnosis of these often devastating conditions that can be quickly translated to clinical practice, 2] permit improved genetic counseling and testing for concerned families, and 3] offer an enhanced understanding of the underlying molecular processes of the developing human brain which can inform the conception of potential future therapies or interventions. These treatments may apply not only to our specific, often under-served, patient populations, but also more broadly to numerous patients impacted by the relatively common symptoms of seizures and intellectual and motor impairments. Hence, our research works to reduce the burden of neurologic disease on our human society and does so with important short and long-term implications.