The Odds of Small Things: Polygenic Foundations and Phenotypic Variability of Neurodevelopmental Disorders

Anthony-Samuel LaMantia to present at Precision Neuroscience Conference
  • Anthony-Samuel LaMantia, Ph.D., Professor, and Director of the Center for Neurobiology Research, Fralin Biomedical Research Institute at VTC; Department of Biological Sciences, College of Science; Department of Pediatrics, VTC School of Medicine

  • Wed. May 25, 2022

  • 8:55 – 9:20 a.m.

  • Washington Room, Hotel Roanoke

Abstract: Most neurodevelopmental disorders are polygenic in their origin; however, there is very little understanding of the relationship between this complex genetic architecture and the even more chimerical phenotypes that characterize these diseases. We have used the copy number variant neurodevelopmental disorder 22q11.2 Deletion Syndrome (“22q11DS”; also known as DiGeorge Syndrome) to begin to understand the impact of a polygenic disruption on key mechanisms for neural circuit development. Using genomically valid mouse models of the full heterozygous deletion underlying 22q11DS, as well as mutations of single genes within the region, we have found that essential developmental mechanisms: patterning, progenitor specification/ proliferation, neuronal migration, process growth and synapse formation are all disrupted by diminished dosage of subsets of genes within the 32MB minimal critical deleted region associated with 22q11DS. Our observations also demonstrate that while these phenotypes, and their relationship to dosage changes of the heterozygously deleted 22q11 genes, are statistically robust, they vary substantially, even in otherwise isogenic mice in which the full set of 22q11 gene orthologues have been deleted. Thus, our results suggest that polygenic neurodevelopmental disorders most likely result from small disruptions of critical cellular mechanisms of neural development that concatenate in any individual to establish an intrinsically variable, individually distinct signature of neural circuit pathology and behavioral dysfunction.

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