Multiomic analyses implicate a neurodevelopmental program in the pathogenesis of cerebral arachnoid cysts
Adam J Kundishora1, Garrett Allington2,3, Stephen McGee4
1Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
Nature Medicine
|March 6, 2023
Summary
Damaging de novo variants (DNVs) are linked to cerebral arachnoid cysts (ACs), a common developmental brain lesion. This suggests ACs may indicate underlying neurodevelopmental issues, warranting genetic testing.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Cerebral arachnoid cysts (ACs) are common but poorly understood developmental brain lesions.
- Understanding AC pathogenesis is crucial for diagnosing and managing neurodevelopmental disorders.
Purpose of the Study:
- To elucidate the pathogenesis of cerebral arachnoid cysts (ACs) through an integrated multiomics approach.
- To identify genetic factors and developmental pathways involved in AC formation.
Main Methods:
- Integrated analysis of 617 patient-parent (trio) exomes.
- Analysis of 152,898 human brain and mouse meningeal single-cell RNA sequencing transcriptomes.
- Natural language processing of patient medical records.
Main Results:
- Damaging de novo variants (DNVs) were significantly enriched in AC patients.
- Seven genes showed an exome-wide significant DNV burden, enriched for chromatin modifiers.
- Four AC subtypes were identified, with clinical severity correlating with DNV presence.
Conclusions:
- Epigenomic dysregulation due to DNVs implicates AC pathogenesis.
- ACs may serve as radiographic indicators of neurodevelopmental pathology.
- A multiomics approach is valuable for studying sporadic structural brain diseases.
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