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

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.