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

Kun Leng; Cathryn R Cadwell; Walter P Devine; Tarik Tihan; Zhongxia Qi; Nilika S Singhal; Orit A Glenn; Sherry Kamiya; Arun P Wiita; Amy C Berger; Joseph T Shieh; Erron W Titus; Mercedes F Paredes; Vaibhav Upadhyay

doi:10.1212/NXG.0000000000200142

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

Neurol Genet. 2024 Apr 3;10(2):e200142. doi: 10.1212/NXG.0000000000200142. eCollection 2024 Apr.

Affiliation

¹ From the Medical Scientist Training Program (K.L., E.W.T.); Department of Pathology (C.R.C., W.P.D., T.T., S.K.); Department of Neurological Surgery (C.R.C.); Weill Institute for Neuroscience (C.R.C., M.F.P.); Department of Laboratory Medicine (Z.Q., A.P.W., E.W.T.); Division of Epilepsy (N.S.S., M.F.P.), Department of Neurology; Department of Radiology and Biomedical Imaging (O.A.G.); Department of Bioengineering and Therapeutic Sciences (A.P.W.), University of California, San Francisco; Chan Zuckerberg Biohub (A.P.W.), San Francisco; Department of Medicine (A.C.B., V.U.), University of California San Francisco; Denali Therapeutics (A.C.B.), South San Francisco; Medical Genetics (J.T.S.), Department of Pediatrics, University of California, San Francisco.

Abstract

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.