High incidence of Y-chromosome mosaicism in male and female individuals with MOGHE

Abstract Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) is a recently discovered histopathological lesion entity. Approximately half of affected individuals carry a pathogenic brain mosaicism in the X-linked SLC35A2 gene, and all suffer from epilepsy. In this work, we extended the search for genetic alterations of MOGHE by investigating sex chromosome copy number alterations in 29 brain tissue samples from 19 males and 10 females with histopathologically confirmed MOGHE. Twenty individuals carried pathogenic SLC35A2 variants, while no genetic alteration was identified in nine individuals using targeted deep panel sequencing. Interestingly, DNA methylation-derived copy number variation (CNV) plots revealed significant gains of the Y chromosome in 16/19 males (84.2%) and in 5/10 females (50%). These findings were validated by chromogenic and fluorescent in situ hybridisation (ISH), PCR amplification of Y-specific sequences, and microscopic localisation of cells with Y-chromosomal gain in clusters of oligodendroglial hyperplasia. PCR and ISH demonstrated lesion-restricted Y-chromosome gains, absent in the overlying non-lesional neocortex. Together with pathogenic variants in the X-chromosomal SLC35A2 gene, Y-chromosomal sequences detected in phenotypic females and mosaic Y chromosome gains in males provide a genomic correlate for all cases of MOGHE. Based on SLC35A2 mutational status and Y-chromosome copy number changes, we stratified the cohort into three subgroups: SLC35A2-mutant without Y gain (SLC+/Y–, n = 8), SLC35A2-mutant with Y gain (SLC+/Y+, n = 12), and SLC35A2-wild type with Y gain (SLC–/Y+, n = 9). These genetically defined subgroups also differed in their clinical presentation, with individuals from group 2 having the earliest disease onset and the largest lesion volume on MRI. These findings expand the genetic spectrum of epileptogenic cortical malformations and highlight a potentially overlooked role of sex chromosome biology in this focal epilepsy. Competing Interest Statement The authors have declared no competing interest. Funding Statement This study was funded by: IB, KK, LH, KrK, and EC were supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) project number 460333672-CRC1540 Exploring Brain Mechanics. Confocal microscopy was enabled on a Leica Stellaris 8 laser scanning microscope, funded by Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) project 441730715. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Medical Faculty of the Friedrich-Alexander University Erlangen-Nuremberg (#193_18B, 18-192_1-Bio) gave ethical approval to this work University of Muenster (2015-088-f-S) gave ethical approval to this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data produced in the present work are contained in the manuscript