Dissecting the genetics of spectrum of Epilepsies with Eyelid Myoclonia by exome sequencing

Objectives: Epilepsy with Eyelid Myoclonia (EEM) spectrum, is a generalized form of epilepsy characterized by eyelid myoclonia with or without absences, eye closure-induced seizures with EEG paroxysms, and photosensitivity. Based on the specific clinical features, age of onset and familial occurrence, a genetic cause has been postulated. Pathogenic variants in CHD2, SYNGAP1, NEXMIF and RORB and GABRA1 have been reported in individuals with photosensitivity and eyelid myoclonia, but whether other genes are also involved, or a single gene is uniquely linked with EEM, or its subtypes, is not yet known. We aimed to dissect the genetic aetiology of EEM. Methods: we studied a cohort of 105 individuals by using whole-exome sequencing. Individuals were divided into two groups: EEM- (isolated EEM) and EEM+ (EEM accompanied by intellectual disability, ID, or any other neurodevelopmental/psychiatric disorder) RESULTS: We identified nine variants classified as pathogenic/likely pathogenic in the entire cohort (8.57%); among these eight (five in CHD2, one in NEXMIF, one in SYNGAP1 and one in TRIM8) were found in the EEM+ sub-cohort (28.57%). Only one variant (IFIH1) was found in the EEM- sub-cohort (1.29%); however, since the phenotype of the proband did not fit with published data, additional evidence is needed before considering IFIH1 variants and EEM- an established association. Burden analysis did not identify any single burdened gene or gene set. Significance: Our results suggest that for EEM, as for many other epilepsies, the identification of a genetic cause is more likely with co-morbid ID and/or other neurodevelopmental disorders. Pathogenic variants were mostly found in CHD2 and the association of CHD2-EEM+ can now be considered a reasonable gene-disease association. We provide further evidence to strengthen the association of EEM+ with NEXMIF and SYNGAP1. Possible new associations between EEM+ and TRIM8, and EEM- and IFIH1, are also reported. While we provided robust evidence for gene variants associated with EEM+, the core genetic aetiology of EEM- remains to be elucidated.