PROJECT SUMMARY
Coffin-Siris syndrome (CSS), Nicolaides-Baraitser syndrome (NCBRS) and Cornelia de Lange syndrome (CdLS)
are rare genetic disorders of chromatin modification characterized by varying degrees of intellectual disability,
seizures, hypotonia, and facial and digit abnormalities. CSS-associated mutations in the same gene do not
necessarily present with identical phenotypes, suggesting that there exists naturally occurring genetic variants
within the genetic background of the patient that modify disease presentation. This proposal tests the hypothesis
that candidate genetic modifiers are responsible for the varied severity of CSS, NCBRS, and CdLS and seeks
to identify such modifiers using D. melanogaster. There are not enough CSS patients to provide adequate
statistical power to identify these modifiers using human data. However, genes associated with CSS and related
disorders are highly conserved across taxa, facilitating the use of model organisms, such as the fruit fly
Drosophila melanogaster, to elucidate possible genetic modifiers and mechanisms of pathogenesis. Flies can
be economically reared in large numbers within a controlled genetic background and exhibit quantifiable changes
in behavior upon perturbation of fly orthologs of CSS-, NCBRS-, and CdLS-associated genes. Flies with
decreased expression of genes co-regulated upon perturbation of CSS-, NCBRS-, and CdLS-associated fly
orthologs will be assessed for behavioral changes and the presence of epistatic genetic interactions. Resulting
genetic interactions or changes in behavior indicate that gene may be a candidate genetic modifier. The impact
of genetic background on CSS fly phenotypes will be assessed on transgenic flies with normal or mutant copies
of human ARID1B, the most commonly mutated gene in CSS, as well as on flies with decreased expression of
osa, the fly ortholog for ARID1B. Genome-wide association analysis will be used to identify potential genetic
modifiers, and subsequent functional validation will provide evidence that these candidate modifiers likely play a
role in CSS disease development. These genetic modifiers will serve as plausible targets for further study on the
pathogenesis, diagnosis, treatment and management of CSS and related disorders. This proposal provides the
opportunity for the candidate to receive training in areas related to her long-term career goals, including
bioinformatics, statistical analyses, and a complex-trait approach to characterize Mendelian diseases through
the use of animal models. In addition to laboratory training, the environment and resources available at the
Clemson Center for Human Genetics will provide the candidate with additional opportunities to engage with
clinicians and participate in genetics education and outreach activities.