top of page

2023 Highlights


March 06, 2023

Volume 29, ahead of print

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

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...


February 16, 2023

Volume 186, Issue 4

The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus

The choroid plexus (ChP) is the blood-cerebrospinal fluid (CSF) barrier and the primary source of CSF. Acquired hydrocephalus, caused by brain infection or hemorrhage, lacks drug treatments due to obscure pathobiology. Our integrated, multi-omic investigation of post-infectious hydrocephalus (PIH) and post-hemorrhagic hydrocephalus (PHH) models revealed that lipopolysaccharide and blood breakdown products trigger highly similar TLR4-dependent immune responses at the ChP-CSF interface. The resulting CSF "cytokine storm", elicited from...


January 01, 2023

Volume 142, Issue 1

De novo mutations in the BMP signaling pathway in lambdoid craniosynostosis

Lambdoid craniosynostosis (CS) is a congenital anomaly resulting from premature fusion of the cranial suture between the parietal and occipital bones. Predominantly sporadic, it is the rarest form of CS and its genetic etiology is largely unexplored. Exome sequencing of 25 kindreds, including 18 parent-offspring trios with sporadic lambdoid CS, revealed a marked excess of damaging (predominantly missense) de novo mutations that account for ~ 40% of sporadic cases. These mutations clustered in the BMP signaling cascade (P = 1.6 × 10-7), including mutations in...

Singh AK, Viviano S, Allington G, et al. A novel SMARCC1 -mutant BAFopathy implicates epigenetic dysregulation of neural progenitors in hydrocephalus. Preprint. medRxiv. 2023;2023.03.19.23287455. Published 2023 Mar 20. doi:10.1101/2023.03.19.23287455
Mehta NH, Greenberg ABW, Kahle KT. The Efficacy of Endoscopic Third Ventriculostomy for Idiopathic Normal Pressure Hydrocephalus [published online ahead of print, 2023 Aug 23]. World Neurosurg. 2023;S1878-8750(23)01184-1. doi:10.1016/j.wneu.2023.08.071
Khoshkhoo S, Wang Y, Chahine Y, et al. Contribution of Somatic Ras/Raf/Mitogen-Activated Protein Kinase Variants in the Hippocampus in Drug-Resistant Mesial Temporal Lobe Epilepsy. JAMA Neurol. 2023;80(6):578-587. doi:10.1001/jamaneurol.2023.0473
Stokum JA, Shim B, Negoita S, et al. Cation flux through SUR1-TRPM4 and NCX1 in astrocyte endfeet induces water influx through AQP4 and brain swelling after ischemic stroke. Sci Signal. 2023;16(788):eadd6364. doi:10.1126/scisignal.add6364
Timberlake AT, McGee S, Allington G, et al. De novo variants implicate chromatin modification, transcriptional regulation, and retinoic acid signaling in syndromic craniosynostosis. Am J Hum Genet. 2023;110(5):846-862. doi:10.1016/j.ajhg.2023.03.017
Zhao S, Mekbib KY, van der Ent MA, et al. Genetic dysregulation of an endothelial Ras signaling network in vein of Galen malformations. Preprint. bioRxiv. 2023;2023.03.18.532837. Published 2023 Mar 21. doi:10.1101/2023.03.18.532837
Pinard A, Ye W, Fraser SM, et al. Rare variants in ANO1, encoding a calcium-activated chloride channel, predispose to moyamoya disease [published online ahead of print, 2023 May 30] [published correction appears in Brain. 2023 Aug 18;:]. Brain. 2023;awad172. doi:10.1093/brain/awad172
Qureshi HM, Mekbib KY, Allington G, et al. Familial and syndromic forms of arachnoid cyst implicate genetic factors in disease pathogenesis. Cereb Cortex. 2023;33(6):3012-3025. doi:10.1093/cercor/bhac257
Kundishora AJ, Kahle KT. Epigenomic dysregulation correlates with arachnoid cyst formation and neurodevelopmental symptoms. Nat Med. 2023;29(3):541-542. doi:10.1038/s41591-023-02239-1
Duy PQ, Rakic P, Alper SL, et al. A neural stem cell paradigm of pediatric hydrocephalus. Cereb Cortex. 2023;33(8):4262-4279. doi:10.1093/cercor/bhac341
Duy PQ, Timberlake AT, Lifton RP, Kahle KT. Molecular genetics of human developmental neurocranial anomalies: towards "precision surgery". Cereb Cortex. 2023;33(6):2912-2918. doi:10.1093/cercor/bhac249
Duy PQ, Kahle KT. "Floppy brain" in congenital hydrocephalus. Cereb Cortex. 2023;33(15):9339-9342. doi:10.1093/cercor/bhad206
Kruszka P, Rolle M, Kahle KT, Muenke M. Muenke Syndrome. In: Adam MP, Mirzaa GM, Pagon RA, et al., eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; May 10, 2006.
Kahle KT, Duran D, Smith ER. Increasing precision in the management of pediatric neurosurgical cerebrovascular diseases with molecular genetics. J Neurosurg Pediatr. 2023;31(3):228-237. Published 2023 Jan 6. doi:10.3171/2022.12.PEDS22332
Robert SM, Reeves BC, Kiziltug E, et al. The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus. Cell. 2023;186(4):764-785.e21. doi:10.1016/j.cell.2023.01.017
Kundishora AJ, Allington G, McGee S, et al. Multiomic analyses implicate a neurodevelopmental program in the pathogenesis of cerebral arachnoid cysts [published online ahead of print, 2023 Mar 6]. Nat Med. 2023;10.1038/s41591-023-02238-2. doi:10.1038/s41591-023-02238-2
Timberlake AT, Kiziltug E, Jin SC, et al. De novo mutations in the BMP signaling pathway in lambdoid craniosynostosis. Hum Genet. 2023;142(1):21-32. doi:10.1007/s00439-022-02477-2
bottom of page