Investigation of genes in progressive myoclonic epilepsies with all whole exome sequencing

Progressive Myoclonus Epilepsy (PME) is a disease-induced myoclonus, tonic-clonic seizures, and progressive neurological manifestations. The differential diagnosis for PME subgroups is rather challenging, as most PME types have clinically similar characteristics and they are genetically heterogeneous. PMEs can clinically be classified in two main groups via evaluating the cognitive status of affected individuals. PME subtypes with normal cognitive functioning include Unverricht-Lundborg Disease (ULH) and Action myoclonus-renal failure syndrome. On the other hand, in PME subtypes such as Lafora Disease (LD) and Neuronal Ceroid Lipofuscinosis (CLN), there is cognitive decline as the disease progresses. Herein, we set out to analyze a cohort of PME patients with clinically overlapping features in order to provide molecular diagnosis, find new PME genes and establish the genetic profile of PME patients specific to our country via this pilot study. Since PME is a rare disease, the outcome of our project also overlaps with rare disease studies. In this study, we have performed genetic analyses in 21 patieents from 18 distinct families. In this context, we have undertaken a serial analysis strategy: (i) Investigation of EPM2A and NHLRC1 genes related to Lafora Disease -a rather common form of PME- by Sanger sequencing (ii) Whole exome sequencing to identify both known and new PME genes. In the framework of this study, we have analyzed the intense genetic heterogeneity in PME patient group with the aim of providing patient specific results. As a result of the study, variants have been identified in EMP2A, NHLRC1, SCARB2 and KCTD7 genes associated with different subgroups and in a single patient, a variant in a gene that may be associated with the disease has been identified. In four patients, a variant that could be associated with or associated with the disease could not be identified and candidate genes were selected.