Autism spectrum disorder (ASD) has a strong genetic basis and a large number of genes have been identified that confer high risk for ASD in humans. But, it remains unknown how genetic risk translates into the phenotypic severity of ASD for a given individual.
It is possible that the phenotypic severity of a heterozygous de novo autism gene mutation can be altered/modified by second site, heterozygous loss of function mutations in the genetic background of an individual.
To test this hypothesis, we use Drosophila as a model system. First, we demonstrate that heterozygous ASD mutations do not impair baseline synaptic transmission or presynaptic homeostatic plasticity (PHP). Next, we systematically combined a heterozygous ASD mutation with heterozygous chromosomal deletions that uncover defined regions of the Drosophila genome. In each double-heterozygous combination, we assessed the expression of PHP by direct quantification of synaptic transmission, entailing more than one thousand intracellular recordings.
We have screened two thirds of the Drosophila genome and identified 40 loci that impair homeostatic plasticity when combined with a heterozygous autism mutation. We selected five of these loci and tested each against four additional ASD genes; CHD2, CHD8, WDFY3 and ASH1L. Assaying this set of double heterozygous mutant combinations, we discovered that more than two-thirds of the double heterozygous combinations caused impaired homeostatic plasticity. RNAseq analysis of double heterozygous mutant combinations, and additional phenotypic characterization of double heterozygous mutant at the electrophysiological and ultrastructural levels will be presented.
We propose that impaired homeostatic plasticity could be a common pathophysiology related to the phenotypic severity of ASD caused by a rare de novo mutation in a given individual. By extension, our data may define a means by which diverse categories of ASD gene mutations could converge upon a common human phenotype.