Cell-Type Specificity of Mosaic Chromosome 1q Gain Resolved by snRNA-seq in a Case of Epilepsy With Hyaline Protoplasmic Astrocytopathy.

Objectives: Mosaic gain of chromosome 1q (chr1q) has been associated with malformation of cortical development (MCD) and epilepsy. Hyaline protoplasmic astrocytopathy (HPA) is a rare neuropathologic finding seen in cases of epilepsy with MCD. The cell-type specificity of mosaic chr1q gain in the brain and the molecular signatures of HPA are unknown.
Methods: We present the case of a child with pharmacoresistant epilepsy who underwent epileptic focus resections at age 3 and 5 years and was found to have mosaic chr1q gain and HPA. We performed single-nuclei RNA sequencing (snRNA-seq) of brain tissue from the second resection.
Results: snRNA-seq showed increased expression of chr1q genes specifically in subsets of neurons and astrocytes. Differentially expressed genes associated with inferred chr1q gain included AKT3 and genes associated with cell adhesion or migration. A subpopulation of astrocytes demonstrated marked enrichment for synapse-associated transcripts, possibly linked to the astrocytic inclusions observed in HPA.
Discussion: snRNA-seq may be used to infer the cell-type specificity of mosaic chromosomal copy number changes and identify associated gene expression alterations, which in the case of chr1q gain may involve aberrations in cell migration. Future studies using spatial profiling could yield further insights on the molecular signatures of HPA.
Competing Interests: K. Leng was supported by NIA F30AG066418. E.W. Titus was supported by Damon Runyon Fellowship DRG122-22. M.F. Paredes was supported by the Roberta and Oscar Gregory Endowment in Stroke and Brain Research, Chan Zuckerberg Biohub, and NINDS 1R21NS123461-01A1. V. Upadhyay was supported by NHLBI K08HL165106. C.R. Cadwell was supported by NINDS K08NS126573 and U01NS132353, the Weill Neurohub, the Shurl and Kay Curci Foundation, and Citizens United for Research in Epilepsy (CURE). A.C. Berger is currently employed at Denali Therapeutics but was not affiliated with Denali during her clinical involvement with the patient. All other authors report no disclosures relevant to the manuscript. Go to Neurology.org/NG for full disclosures.
(Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)