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

Autor: Kundishora AJ; Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA., Allington G; Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.; Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA., McGee S; GeneDx, Gaithersburg, MD, USA., Mekbib KY; Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.; Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA., Gainullin V; GeneDx, Gaithersburg, MD, USA., Timberlake AT; Hansjörg Wyss Department of Plastic Surgery, New York University Langone Medical Center, New York, NY, USA., Nelson-Williams C; Department of Genetics, Yale University School of Medicine, New Haven, CT, USA., Kiziltug E; Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA., Smith H; Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.; Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA., Ocken J; Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA., Shohfi J; Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA., Allocco A; Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA., Duy PQ; Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA., Elsamadicy AA; Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA., Dong W; Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA., Zhao S; Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA., Wang YC; Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA., Qureshi HM; Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA., DiLuna ML; Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA., Mane S; Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.; Yale Center for Genomic Analysis, Yale University, West Haven, CT, USA., Tikhonova IR; School of Pharmacy, Queen's University Belfast, Belfast, UK., Fu PY; Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA., Castaldi C; Yale Center for Genomic Analysis, Yale University, West Haven, CT, USA., López-Giráldez F; Yale Center for Genomic Analysis, Yale University, West Haven, CT, USA., Knight JR; Yale Center for Genomic Analysis, Yale University, West Haven, CT, USA., Furey CG; Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA., Carter BS; Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA., Haider S; School of Pharmacy, University College London, London, UK., Moreno-De-Luca A; Department of Radiology, Autism and Developmental Medicine Institute, Genomic Medicine Institute, Geisinger, Danville, PA, USA., Alper SL; Division of Nephrology and Vascular Biology Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA., Gunel M; Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA., Millan F; GeneDx, Gaithersburg, MD, USA., Lifton RP; Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA., Torene RI; GeneDx, Gaithersburg, MD, USA., Jin SC; Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA., Kahle KT; Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA. kahle.kristopher@mgh.harvard.edu.; Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA. kahle.kristopher@mgh.harvard.edu.; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA. kahle.kristopher@mgh.harvard.edu.; Broad Institute of MIT and Harvard, Cambridge, MA, USA. kahle.kristopher@mgh.harvard.edu.
Jazyk: angličtina
Zdroj: Nature medicine [Nat Med] 2023 Mar; Vol. 29 (3), pp. 667-678. Date of Electronic Publication: 2023 Mar 06.
DOI: 10.1038/s41591-023-02238-2
Abstrakt: 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 -33 ). 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.
(© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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