Objective: Epileptic encephalopathies are a devastating group of electroclinical syndromes with early onset of drugâ?Âresistant seizures in which the epileptiform abnormalities may contribute to progressive dysfunction or developmental stagnation and consequent cognitive and behavioral impairments.
A genetic etiology can be identified in a considerable proportion of patients with epileptic encephalopathy. Most have de-novo dominant mutations, but a growing proportion of patients has a polygenic inheritance in which the interaction of several genetic variants is responsible for the phenotype.
The increased efficiency and the reduced cost of next-generation sequencing tests promoted their implementation into the routine diagnostic process. Whole-exome sequencing (WES) is a technique for comprehensively sequencing all the protein-coding regions of the genome (~20,000 genes). It has proven successful in identifying undiagnosed genetic disorders in many patients with a broad phenotypic spectrum.
Methods: We report our experience in the use of WES as a first-tier molecular test in 40 patients with undiagnosed epileptic encephalopathies at Oasi Research Institute-IRCCS, Troina, Italy. The test was performed on probands and their unaffected parents (trio analysis). Each genetic variant found has been compared to known variables in main polymorphism and mutation databases and a deeply in silico analysis for predicting pathogenicity was performed. All variants found were confirmed by sanger sequencing.
Results: About a third of patients received a genetic diagnosis. And WES proved to have a good cost-effectiveness ratio. Our data highlight the clinical utility and feasibility of WES in individuals with undiagnosed forms of epileptic encephalopathies.
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