Many neurological disorders have a genetic etiology. Human genetics projects in the lab aim to identify novel disease genes and alleles that underlie a broad range of neurodevelopmental phenotypes. Projects start with the clinical characterization of patients seen either locally at the University of Michigan Medical Center, or by one of our international collaborators. Whole exome and genome sequencing are used to identify the genetic causes of neurodevelopmental disorders. Functional tests are designed to evaluate the pathogenicity of patient alleles and further inform genetic variants of unknown significance. These findings often provide preliminary insights into disease mechanisms and help direct subsequent disease modeling studies.
The human cerebral cortex is the part of the brain that integrates sensations, executes decisions, and is responsible for cognition and perception. Given its functional importance, it is not surprising that diseases of the cerebral cortex are major causes of morbidity and mortality. During embryonic development, all of the neurons in the cortex are generated from a population of multipotent neural stem cells. Research in the lab is aimed at understanding the epigenetic and molecular mechanisms of human disease genes in the maintenance and proliferation of neural stem cells. How stem cell multipotency, self-renewal, and neurogenesis are regulated and coordinated to generate complex lineages in a fixed temporal order is essential for understanding the pathogenesis of neurodevelopmental disorders and human encephalization. A major challenge to investigating human neurodevelopmental disorders has been the lack of affected tissue. The capacity of human pluripotent stem cells (hPSC) to differentiate into the full complement of neural tissue, opens an exciting new avenue to investigate human-specific features of neurodevelopment. We use both hPSC and transgenic mouse models to investigate the pathogenic mechanisms of human neurodevelopmental disease genes identified in the lab.