2096 Cerebellar Overgrowth Subtype of Chiari Malformation Type 1 and Genetic Dysregulation of PI3K Signaling

INTRODUCTION: Chiari malformation type 1 (CM1) is the most common disorder of the craniocervical junction characterized by herniation of the cerebellar tonsils causing compression of neural tissue and obstruction of CSF flow. Despite its prevalence, our poor understanding of its molecular pathogenesis has contributed to significant variability in clinical and surgical outcomes. METHODS: We performed WES of 1585 Chiari patient-parent trios to identify de novo variants (DNVs) and uncover exome-wide significant and high-confidence CM1 genes. Integrative analysis was performed of CM1 gene enriched modules created from spatiotemporal transcriptomic atlases of the cerebellum, dura, and occipital bone from both bulk- and single-cell RNA seq datasets. Natural language processing of electronic medical records was used for phenotypic characterization and neuroimaging was analyzed for craniometric abnormalities. RESULTS: DNV analysis found significant enrichment of protein-damaging DNVs (p=1.00 × 10-59) with 15 genes achieving exome-wide significance and 85 genes meeting criteria for high-confidence CM1 genes. Gene ontology analysis of these gene sets found significant enrichment of the PI3K signaling pathway (p=7.95 × 10-4) with identical predicted-deleterious missense DNVs in PIK3R2, a subunit of the PI3K enzyme, we found in four unrelated CM1 patients as well as multiple variants in two other PI3K signaling genes, PIK3CA and PTEN. CONCLUSIONS: The PI3K signaling pathway is critical for cell proliferation and mutations in PIK3R2 have been associated with brain overgrowth. While CM1 has historically been associated with posterior fossa bony constriction, our study not only demonstrates a significant genetic contribution to CM1 pathogenesis but suggests a CM1 subtype characterized by cerebellar overgrowth and genetic dysregulation of the PI3K pathway.