Date of Award

January 2024

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Kristopher T. Kahle

Second Advisor

Murat Gunel

Abstract

Cerebral arachnoid cysts (ACs) are the most common space-occupying lesion of thehuman brain but we know very little about its pathogenesis and association with other neurological phenotypes complicating clinical management.

To better understand AC pathogenesis and clinical presentation, we conducted wholeexomesequencing of 617 patient-parent trios, analysis of human brain and mouse meningeal single-cell RNA sequencing and natural language processing of patient medical records, the largest and only integrative genomic study of ACs to date.

We found seven genes: ADNP, ARID1B, KDM5C, PURA, FOXP1, MAP2K1 andSCN2A, had an exome-wide statistically significant burden of de novo variants. Our AC candidate genes were most often transcription regulating genes involved in early fetal neural and meningeal development and associated with epilepsy and autism. Our novel clustering of textextracted patient phenotypes identified four distinct clinical AC clusters that correlated with DNV enrichment.

Ultimately, our findings suggest that many ACs results from epigenetic dysregulation ofearly neural and meningeal development resulting in other neurological phenotypes as well that may benefit from genetic testing and early neurobehavioral therapy rather than invasive neurosurgical management.

Comments

This is an Open Access Thesis.

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