Common genetic epilepsies, pathogenicity of genes/variants, and genetic dependence

The remarks in the letter [ [1] McKee J.L. Karlin A. deCampo D. Helbig I GLUT1, GGE, and the resilient fallacy of refuted epilepsy genes. Seizure. 2023; Abstract Full Text Full Text PDF Scopus (1) Google Scholar ] reveal the authors' deep insight into current challenges in genetic studies. They refer to three critical questions: how to identify the causative genes of common diseases like genetic generalized epilepsy (GGE); how to determine gene-disease associations, especially for some genes with questionable epileptogenic effects such as EFHC1 and CACNA1H; and how to evaluate the pathogenicity of variants in a given gene and their clinical implication, as in the case of variants of SLC2A1 (encoding GLUT1). There is an old Chinese saying that heroes always have similar perspectives. Actually, the paper the letter comments on refers to our initial work focusing on trio-based exome sequencing of epilepsy genes [ [2] Lin Z.J. Li B. Lin P.X. 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 ]. We highly appreciate that the authors of the letter [ [1] McKee J.L. Karlin A. deCampo D. Helbig I GLUT1, GGE, and the resilient fallacy of refuted epilepsy genes. Seizure. 2023; Abstract Full Text Full Text PDF Scopus (1) Google Scholar ] identified these three critical points in such a modest paper.