Date of Award
Spring 2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Experimental Pathology
First Advisor
Kahle, Kristopher
Abstract
Cerebral arachnoid cysts (ACs) are among the most common human developmental brain lesions, yet, because ACs are not possible to reliably model in lower mammals, the pathogenic mechanisms driving AC formation remain poorly understood. To begin to elucidate AC pathogenesis, we performed an integrated analysis of 617 proband-parent exome trios, 152,898 brain and meningeal single-cell transcriptomes, and artificially-intelligent natural language processor data of proband medical records. We found damaging de novo variants (DNVs) were highly enriched in AC probands versus controls (P = 1 .57 × 10-33). Seven genes harbored an exome-wide significant DNV burden. AC-associated genes are enriched for chromatin modifiers and converged in midgestational transcription networks essential for neural and meningeal development. Unsupervised clustering of patient phenotypes identified four AC subtypes and clinical severity correlated with the presence of a damaging DNV. These results shed unique insight into the coordinated regulation of brain and meningeal development and implicate epigenomic dysregulation due to protein-damaging DNVs in AC pathogenesis, suggesting associated neurodevelopmental phenomena in the context of AC may be largely unrelated to mass effect, but rather due to an underlying common defect in early neurodevelopment. In the appropriate clinical context, ACs may be considered radiographic harbingers of neurodevelopmental pathology warranting additional genetic testing and neurobehavioral follow-up. These data also highlight the utility of a systems-level, multi-omics approach to elucidate sporadic structural brain disease, describing novel methodologies which may be broadly-applicable to the further study of a variety of pediatric neurological defects.
Recommended Citation
Allington, Garrett, "Pediatric Cerebral Arachnoid Cysts are Genetically-encoded Harbingers of Neurodevelopmental Pathology" (2023). Yale Graduate School of Arts and Sciences Dissertations. 1009.
https://elischolar.library.yale.edu/gsas_dissertations/1009
