Multiomic analyses implicate a neurodevelopmental program in the pathogenesis of cerebral arachnoid cysts

Authors

• Adam J. Kundishora, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
• Garrett Allington, Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
• Stephen McGee, GeneDx, Gaithersburg, MD, USA.
• Kedous Y. Mekbib, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
• Vladimir Gainullin, GeneDx, Gaithersburg, MD, USA.
• Andrew T. Timberlake, Hansjörg Wyss Department of Plastic Surgery, New York University Langone Medical Center, New York, NY, USA.
• Carol Nelson-Williams, Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
• Emre Kiziltug, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
• Hannah Smith, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
• Jack Ocken, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
• John Shohfi, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
• August Allocco, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
• Phan Q. Duy, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
• Aladine A. Elsamadicy, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
• Weilai Dong, Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA.
• Shujuan Zhao, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
• Yung-Chun Wang, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
• Hanya M. Qureshi, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
• Michael L. DiLuna, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
• Shrikant Mane, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
• Irina R. Tikhonova, School of Pharmacy, Queen's University Belfast, Belfast, UK.
• Po-Ying Fu, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
• Christopher Castaldi, Yale Center for Genomic Analysis, Yale University, West Haven, CT, USA.
• Francesc López-Giráldez, Yale Center for Genomic Analysis, Yale University, West Haven, CT, USA.
• James R. Knight, Yale Center for Genomic Analysis, Yale University, West Haven, CT, USA.
• Charuta G. Furey, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
• Bob S. Carter, Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA.
• Shozeb Haider, School of Pharmacy, University College London, London, UK.
• Andres Moreno-De-Luca, Department of Radiology, Autism and Developmental Medicine Institute, Genomic Medicine Institute, Geisinger, Danville, PA, USA.
• Seth L. Alper, Division of Nephrology and Vascular Biology Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
• Murat Gunel, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.

Document Type

Article

Abstract

Cerebral arachnoid cysts (ACs) are one of the most common and poorly understood types of developmental brain lesion. To begin to elucidate AC pathogenesis, we performed an integrated analysis of 617 patient-parent (trio) exomes, 152,898 human brain and mouse meningeal single-cell RNA sequencing transcriptomes and natural language processing data of patient medical records. We found that damaging de novo variants (DNVs) were highly enriched in patients with ACs compared with healthy individuals (P = 1.57 × 10). Seven genes harbored an exome-wide significant DNV burden. AC-associated genes were 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 data provide insights into the coordinated regulation of brain and meningeal development and implicate epigenomic dysregulation due to DNVs in AC pathogenesis. Our results provide a preliminary indication that, in the appropriate clinical context, ACs may be considered radiographic harbingers of neurodevelopmental pathology warranting genetic testing and neurobehavioral follow-up. These data highlight the utility of a systems-level, multiomics approach to elucidate sporadic structural brain disease.

Medical Subject Headings

Humans; Animals; Mice; Multiomics; Arachnoid Cysts (diagnostic imaging, genetics); Brain (diagnostic imaging); Exome (genetics); Genetic Testing

Publication Date

3-1-2023

Publication Title

Nature medicine

E-ISSN

1546-170X

Volume

29

Issue

3

First Page

667

Last Page

678

PubMed ID

36879130

Digital Object Identifier (DOI)

10.1038/s41591-023-02238-2

Recommended Citation

Kundishora, Adam J.; Allington, Garrett; McGee, Stephen; Mekbib, Kedous Y.; Gainullin, Vladimir; Timberlake, Andrew T.; Nelson-Williams, Carol; Kiziltug, Emre; Smith, Hannah; Ocken, Jack; Shohfi, John; Allocco, August; Duy, Phan Q.; Elsamadicy, Aladine A.; Dong, Weilai; Zhao, Shujuan; Wang, Yung-Chun; Qureshi, Hanya M.; DiLuna, Michael L.; Mane, Shrikant; Tikhonova, Irina R.; Fu, Po-Ying; Castaldi, Christopher; López-Giráldez, Francesc; Knight, James R.; Furey, Charuta G.; Carter, Bob S.; Haider, Shozeb; Moreno-De-Luca, Andres; Alper, Seth L.; and Gunel, Murat, "Multiomic analyses implicate a neurodevelopmental program in the pathogenesis of cerebral arachnoid cysts" (2023). Neurosurgery. 2408.
https://scholar.barrowneuro.org/neurosurgery/2408