GLUT1, GGE, and the resilient fallacy of refuted epilepsy genes

It is with great interest that we read the publication by Lin and collaborators on trio exome sequencing in genetic generalized epilepsy, providing an assessment of monogenic etiologies to the disease burden in one of the most common epilepsies [ [1] Lin Z.J. et al. Clinical application of trio-based whole-exome sequencing in idiopathic generalized epilepsy. Seizure. 2023; (S1059-1311(23)00050-X)https://doi.org/10.1016/j.seizure.2023.02.011 Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar ]. A strong genetic contribution to genetic generalized epilepsies (GGE) has been acknowledged since the early twin studies in the 1940′s, but gene discovery in GGE has been slow, compared to the dramatic success in the developmental and epileptic encephalopathies. In 2023, we find ourselves in a paradoxical situation: genome-wide association studies and exome-wide burden analyses for GGE include thousands of individuals [ [2] Epi25 Collaborative, Chen, S., Neale, B.M. & Berkovic, S.F. Shared and distinct ultra-rare genetic risk for diverse epilepsies: a whole-exome sequencing study of 54,423 individuals across multiple genetic ancestries. medRxiv 2023.02.22.23286310 (2023) doi:10.1101/2023.02.22.23286310. Google Scholar ]. However, none of the large research consortia including Epi4K [ [3] Epi4K ConsortiumEpi4K: gene discovery in 4000 genomes. Epilepsia. 2012; 53: 1457-1467 Crossref PubMed Scopus (69) Google Scholar ], EuroEPINOMICS [ [4] EuroEPINOMICS-RES Consortium, Epilepsy Phenome/Genome Project, & Epi4K ConsortiumDe novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. Am J Hum Genet. 2014; 95: 360-370 Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar ], or Epi25 [ [5] Epi25 Collaborative. Electronic address: [email protected] & Epi25 CollaborativeSub-genic intolerance, ClinVar, and the epilepsies: a whole-exome sequencing study of 29,165 individuals. Am J Hum Genet. 2021; 108: 965-982 Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar ] has ever taken on the task of performing the gold standard analysis used in a diagnostic setting, namely exome sequencing of probands and their parents. This gap has now been addressed by the study by Lin and collaborators. Despite a limited sample size of 60 individuals, their study is a milestone in the history of epilepsy genetics as the authors took on a task that everybody else had avoided so far, a truly heroic effort that needs to be applauded.