Author(s): Rebecca A. MacPherson, Clemson University; Rebecca A. MacPherson, Clemson University; Robert R. H. Anholt, Clemson University; Trudy F. C. Mackay, Clemson University //

ABSTRACT: Coffin-Siris syndrome (CSS) and Nicolaides-Baraitser syndrome (NCBRS) are rare disorders of chromatin modification associated with alterations of subunits within the highly conserved mammalian SWI/SNF complex. CSS and NCBRS patients typically present with intellectual disability, facial and digit abnormalities, seizures, and hypotonia. However, phenotypic presentation and disease severity varies within and across CSS- and NCBRS-associated mutations; individuals with identical genetic alterations do not necessarily present with identical phenotypes. We hypothesize that there are naturally occurring genetic variants segregating in the human population that serve as modifiers of disease severity. Identification of candidate genetic modifiers may lead to insights on the pathogenesis and treatment of CSS, NCBRS, and related disorders, but genome wide association analyses that are used to map genetic variants associated with common human diseases require large sample sizes that are not possible for rare diseases.  Using a bipartite UAS-GAL4 RNA interference system in the model organism Drosophila melanogaster, we have developed a CSS/NCBRS fly model and show that flies with reduced expression of CSS-associated fly orthologs exhibit changes in sleep, activity, and sensorimotor integration. We have identified genes co-regulated with CSS-associated fly orthologs that exhibit similar changes in behavior to our CSS fly models, suggesting that these co-regulated genes may serve as plausible candidate genetic modifiers for CSS and NCBRS. We are currently working to identify epistatic genetic interactions between CSS-associated fly orthologs and co-regulated genes.

Source of Funding: NIH grant 1R01 GM128974 to T.F.C.M. and R.R.H.A., NIH grant F31HD106719 to R.A.M.