The Use of Human Genetics to Identify Genes that Regulate Human Brain Development and Cognition

In the last decade investigators in this IDDRC have made exceptional use of human genetics to identify genes that cause neurological disorders.  Dr. Christopher Walsh has been a pioneer in identifying genes that control the development and function of the human cerebral cortex whose mutation can cause autism and epilepsy as well as mental retardation and other learning disorders. Using human genetics to study Middle-Eastern families with a high incidence of disorders of cognitive function Dr. Walsh and his colleagues are making rapid progress in identifying new genes that control the development of human cognition. These genes include those whose mutation causes Joubert syndrome, bilateral frontoparietal polymicrogyria, periventricular nodular heterotopia, microcephaly with periventriuclar heterotopia,  and double cortin syndrome/X linked lissencephaly to name a few.  The identification of each of these genes have provided new insight into mechanisms that regulate human cognitive function, and  new knowledge of the pathways that control such processes as cerebral cortical size, neuronal migration, and patterning of the human cortex.  Another IDDRC investigator, Dr. Mark Keating has been at the forefront of efforts to use human genetics to understand the biochemical basis of common cardiovascular diseases.  This work has led to the identification of mutations in six different ion channel genes that lead to cardiac arrhythmias in humans.  Dr. Keating has recently discovered that mutations in an L-type voltage sensitive calcium channel gene are the cause of Timothy syndrome a human disorder that results in significant mental retardation and autistic behavior. Another investigator in our IDDRC, Dr. Elizabeth Engle has combined clinical, genetic, and molecular biological approaches to study congenital strabismus.  Dr. Engle has defined several new strabismus syndromes and identified the genes mutated in five of these disorders. The cloning of these genes has revealed that familial forms of strabismus often result from mutations in genes expressed early in gestation that are necessary for the development and connectivity of neurons in the brainstem that normally control the eye muscles.