Abstract Objective Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) is an underrecognized pediatric cortical lesion associated with somatic X‐linked SLC35A2 variants in approximately 50% of individuals. The genetic etiology in individuals without detectable SLC35A2 mutations remains undefined, which limits our understanding of its pathomechanism and clinical characterization. The aim is to identify genetic correlates of MOGHE in individuals lacking pathogenic SLC35A2 variants and to investigate the clinicopathological and genomic correlations. Methods We investigated archival brain tissue of 29 individuals (19 males, 10 females) with histopathologically confirmed MOGHE. Twenty individuals carried SLC35A2 variants, and nine individuals lacked detectable mutations in SLC35A2 or other epilepsy‐related genes. Brain tissue samples were analyzed using DNA methylation‐derived copy number variation (CNV) analysis, polymerase chain reaction (PCR), and chromogenic/fluorescent in situ hybridization (ISH). Results CNV analysis identified Y‐chromosomal material in five of 10 females (50%) and mosaic Y‐chromosome gains in 16 of 19 males (84%), confirmed by PCR and ISH, and associated with lesional tissue. Exploratory stratification of the cohort by SLC35A2 status and Y‐chromosome gain revealed a tendency toward earlier seizure onset, multilobar involvement, and cognitive impairment in patients carrying both SLC35A2 mutations and Y‐chromosome gain; however, these differences did not reach statistical significance in our small cohort. Significance The combined presence of Y‐chromosomal material in females, mosaic Y‐chromosome gains in males, and SLC35A2 variants represents a recurrent genomic feature in patients with MOGHE. These findings suggest that sex‐chromosome anomalies may contribute to the pathobiology of this epilepsy‐associated cortical malformation, highlighting the need to clarify the underlying molecular mechanisms of this clinicohistopathologic entity. Although the root cause, biological consequence, and clinical significance of brain somatic Y‐chromosomal gain remain to be further clarified, our findings identify a previously unrecognized genomic feature of MOGHE and provide a rationale for future research in MOGHE cohorts.
Cecchini et al. (Sat,) studied this question.