Kavli Affiliate: Ellen J. Hoffman
| Authors: Meilin Fernandez Garcia, Kayla Retallick-Townsley, Novin Balafkan, April Pruitt, Elizabeth Davidson, Yi Dai, Sarah E Fitzpatrick, Tzu-Chieh Huang, Alfred Kibowen, Jonathan Warrell, Ran Meng, Zhiyuan Chu, Annabel Sen, Sophie Cohen, Olivia Livoti, Suha Khan, Charlotte Becker, Andre Luiz Teles Silva, Jenny Liu, Grace Dossou, Jen Cheung, Sadaf Ghorbani, P.J. Michael Deans, Marisa DeCiucis, Hongying Shen, Mark Gerstein, Huanyao Gao, Zuoheng Wang, Laura Huckins, Ellen Hoffman and Kristen Brennand
| Summary:
Over three hundred and seventy-three risk genes, broadly enriched for roles in neuronal communication and gene expression regulation, underlie risk for autism spectrum disorder (ASD) and developmental delay (DD). Functional genomic studies of subsets of these genes consistently indicate a convergent role in neurogenesis, but how these diverse risk genes converge on a smaller number of biological pathways in mature neurons is unclear. To uncover shared downstream impacts between neurodevelopmental disorder (NDD) risk genes, here we apply a pooled CRISPR approach to contrast the transcriptomic impacts of targeting 29 NDD loss-of-function genes across human induced pluripotent stem cell (hiPSC)-derived neural progenitor cells, glutamatergic neurons, and GABAergic neurons. Points of convergence vary between the cell types of the brain and are greatest in mature glutamatergic neurons, where they broadly target not just synaptic and epigenetic, but unexpectedly, mitochondrial biology. The strongest convergent networks occur between NDD genes with common clinical associations, biological annotations, and co-expression patterns in the post-mortem brain, suggesting that convergence may one-day inform patient stratification. Altogether, robust convergence in post-mitotic neurons represents a clinically actionable therapeutic window.