Poster #74 - Mudassir Lodi

Identifying Risk Genes Associated with Neural Progenitor Cell (NPC) Hyperproliferation

Lodi, M.K., Millonig, J., Xing, J.

Due to genetic heterogeneity, Autism Spectrum Disorder (ASD) exhibits comorbidity with other neurodevelopmental phenotypes, such as macrocephaly. Macrocephaly is found in ~20% of ASD individuals, with ASD patients exhibiting statistically larger head circumference and brain volume. One possible mechanism to explain the enlarged brain associated with macrocephaly is increased proliferation of neural progenitor cells (NPCs). NPC hyper-proliferation has been associated with some common etiologies of ASD, including 16p11.2 Deletion Syndrome (16pDel). Previous analyses of iPSC-derived NPCs from macrocephalic individuals within idiopathic and 16pDel datasets consistently suggest NPC hyperproliferation involvement, which is mechanistically associated with p53 and mTOR pathway dysregulation. We hypothesize that studying the genetic architecture of neurodevelopmental phenotypes associated with NPC hyper-proliferation, such as macrocephaly, within the p53 and mTOR pathways can provide better insight into the genetic architecture of ASD. In this study, we analyze the genomic variation within idiopathic ASD and 16pDel patients with macrocephaly, focusing on variants within the p53 and mTOR pathways. Additionally, we conducted a whole-genome analysis to identify additional candidate genes that may be of interest. To identify genes that are unique to macrocephaly, we analyzed genomic variation within normocephalic patients pertaining to idiopathic ASD and 16pDel patients, and compare the resulting candidate genes sets to one another. Within idiopathic ASD patients, our analysis identified 7 genes across the two pathways with statistical significance that could be associated with macrocephaly. One of the genes, PRKAB2, was identified in macrocephalic but not normocephalic patients. Examination of these genes through molecular experimentation can provide further insight into their impact on neurodevelopmental disorders.