6533b822fe1ef96bd127d7e5

RESEARCH PRODUCT

Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes

Elena ParriniCarla MariniDavide MeiAnna GaluppiElena CelliniDaniela PucattiLaura ChitiDomenico RutiglianoClaudia BianchiniSimona VirdòDalila De VitaStefania BigoniCarmen BarbaFrancesco MariMartino MontomoliTiziana PisanoAnna RosatiRenzo GuerriniPatrizia AccorsiAnna ArdissoneDomenica BattagliaGianna BertaniGabriella BorgarelloElisabetta CesaroniSara ChiariDuccio Maria CordelliViola DocciniIlaria DonatiElena FontanaCarlo FuscoMattia GentileLucio GiordanoSandra JacintoVincenzo LeuzziSalvatore ManganoMario MastrangeloFederico MelaniLaure ObinoChiara OfferDario PrunaFrancesca RagonaPaolo RicciardelliMichela SalandinAntonino SaporosoFederico SiccaNicola SpecchioKatalin Sterebova

subject

0301 basic medicineProbandMaleCDKL5Drug Resistancemedicine.disease_causeBioinformaticsEpilepsyAnticonvulsantSTXBP1Age of OnsetChildGenetics (clinical)AlleleMutationepilepsy; next-generation sequencing; gene panel; mutationPhenotypeMagnetic Resonance ImagingSettore MED/39 - Neuropsichiatria Infantile3. Good healthPhenotypeChild PreschoolAnticonvulsantsFemaleSequence AnalysisHumanAdolescentGenotypeGenetic Association StudieBiologyMECP203 medical and health sciencesGeneticgene panelGeneticsmedicineHumansGenetic Predisposition to DiseasePreschoolGeneAllelesGenetic Association StudiesGene Expression ProfilingInfant NewbornComputational BiologyInfantMolecular Sequence AnnotationDNASequence Analysis DNANewbornmedicine.disease030104 developmental biologyepilepsynext-generation sequencingmutation

description

Targeted resequencing gene panels are used in the diagnostic setting to identify gene defects in epilepsy. We performed targeted resequencing using a 30-genes panel and a 95-genes panel in 349 patients with drug-resistant epilepsies beginning in the first years of life. We identified 71 pathogenic variants, 42 of which novel, in 30 genes, corresponding to 20.3% of the probands. In 66% of mutation positive patients seizures onset occurred before age 6 months. The 95-genes panel allowed a genetic diagnosis in 22 (6.3%) patients that would have otherwise been missed using the 30-gene panel. About 50% of mutations were identified in genes coding for sodium and potassium channel components. SCN2A was the most frequently mutated gene followed by SCN1A, KCNQ2, STXBP1, SCN8A, CDKL5 and MECP2. Twenty-nine mutations were identified in 23 additional genes, most of them recently associated with epilepsy. Our data show that panels targeting about 100 genes represent the best cost-effective diagnostic option in pediatric drug-resistant epilepsies. They enable molecular diagnosis of atypical phenotypes, allowing to broaden phenotype-genotype correlations. Molecular diagnosis might influence patient's management and translate into better and specific treatment recommendations in some conditions. This article is protected by copyright. All rights reserved

10.1002/humu.23149http://hdl.handle.net/10447/222085