Prospective Identification of Individuals with a Brain Overgrowth Form of Autism
This grant will take a first step towards developing a polygenic risk score for brain overgrowth in a large sample of human neural progenitor cells. Understanding the genetic basis of brain overgrowth will enable the development of this important tool for identification of infants at increased risk for the overgrowth form of autism in the general population.
Joseph Piven, M.D.,
with Mark Zylka, Ph.D. and Jason Stein, Ph.D.
Need/Problem: Early (pre-symptomatic) brain overgrowth has emerged as a primary mechanism underlying the development of later autism in a subset of infants at high familial risk for this disorder. Understanding the genetic basis of brain overgrowth will enable the development of a genetic tool (genetic risk score for brain overgrowth) for identification of infants at increased risk for the overgrowth form of autism in the general population.
Grant Summary: This grant will take a first step towards developing this tool (genetic risk score for brain overgrowth) by first identifying genetic variants associated with precursors of brain overgrowth (hyper-proliferation of neural progenitor cells) in a large sample of human neural progenitor cells.
Goals & Projected Outcomes: The primary goal of this study is to develop a polygenic risk score for brain overgrowth. Subsequent study (not funded in the current grant) will validate this polygenic proliferation risk score by seeing whether it can predict accelerated brain growth in a sample of infants at high familial risk for autism (previously studied by the PI) who were examined prospectively with brain imaging at 6, 12 and 24 months of age, and who were diagnosed with autism at 24 months of age. This polygenic risk score may then be applied to screen infants in the general population for increased genetic risk of autism to undergo a more definitive predictive brain imaging test to determine if they are at ultra-high risk for autism and might benefit from intervention in infancy.
Grant Details: Autism as a Significant Public Health Problem: Autism occurs in approximately one in 68 school age children. Despite a dramatic increase in research world-wide, ASD continues to be a major challenge for affected individuals, their families and communities. Treatments to date have only a modest impact on symptoms and outcome. There is general consensus that earlier, and specifically pre-symptomatic treatment in infancy, will have the greatest impact in ameliorating the effects of this condition.
Brain Overgrowth and Autism: Research from the Piven lab has demonstrated that many individuals with autism show evidence of accelerated surface area (SA) expansion followed by increased brain volume early in life. One possible mechanism behind SA expansion is proliferation of neural progenitor cells early in life. Brain enlargement in autism patients occurs in the 2nd year of life, coincident with the first emergence of autistic symptoms. Measures of brain overgrowth in the first year of life on magnetic resonance imaging (MRI) of the brain have been shown by the Piven Lab to accurately predict which high familial risk infants will go on to have a diagnosis of autism at 24 months of age.
The Neurobiology and Genetics of Brain Overgrowth: Data from human patients with rare mutations and mouse models strongly implicate abnormalities in specific molecular signaling pathways in cortical overgrowth. Collectively, these data point to increases in neural progenitor cell proliferation as a cause of brain overgrowth. The near-term goal of our research is to develop a genetic risk score of brain overgrowth by examining the relationship of specific genetic variants to the range of proliferation in neural progenitor cells, derived from a population sample of human neural progenitor cells.
Application to Autism: Future efforts will validate the genetic risk score in a unique sample of infants at high familial risk with autism who have had longitudinal brain scans at 6, 12 and 24 months of age; diagnostic evidence of autism at age 24 months; and, who have DNA available (specifically, whole exome sequence data). The intermediate term goal will then be to determine if the polygenic risk score is able to predict those infants who develop the brain overgrowth form of autism. Subsequent studies may then apply this genetic risk score to infants in the general population to determine if they are at elevated risk for autism and might then be candidates for a second level screening by brain scan to determine if they are at ultra-high risk for autism. If identified in the first year of life, theoretically, these infants would be candidates for early, pre-symptomatic intervention. Although it is important to note that currently no such interventions in infancy have currently been studied.