title: Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes.
abstract: 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, epilepsy onset occurred before the age of 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 patients' management and translate into better and specific treatment recommendations in some conditions.
authors.affiliation: Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A Meyer Children's Hospital, University of Florence, Florence, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Parrini
authors.affiliation: Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A Meyer Children's Hospital, University of Florence, Florence, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Marini
authors.affiliation: Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A Meyer Children's Hospital, University of Florence, Florence, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Mei
authors.affiliation: Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A Meyer Children's Hospital, University of Florence, Florence, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Galuppi
authors.affiliation: Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A Meyer Children's Hospital, University of Florence, Florence, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Cellini
authors.affiliation: Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A Meyer Children's Hospital, University of Florence, Florence, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Pucatti
authors.affiliation: Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A Meyer Children's Hospital, University of Florence, Florence, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Chiti
authors.affiliation: Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A Meyer Children's Hospital, University of Florence, Florence, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Rutigliano
authors.affiliation: Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A Meyer Children's Hospital, University of Florence, Florence, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Bianchini
authors.affiliation: Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A Meyer Children's Hospital, University of Florence, Florence, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Virdò
authors.affiliation: Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A Meyer Children's Hospital, University of Florence, Florence, Italy.
authors.forename: Dalila
authors.initials: D
authors.lastname: De Vita
authors.affiliation: UOL of Medical Genetics, Ferrara University Hospital, Ferrara, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Bigoni
authors.affiliation: Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A Meyer Children's Hospital, University of Florence, Florence, Italy.
authors.forename: Carmen
authors.initials: C
authors.lastname: Barba
authors.affiliation: Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A Meyer Children's Hospital, University of Florence, Florence, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Mari
authors.affiliation: Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A Meyer Children's Hospital, University of Florence, Florence, Italy.
authors.forename: Martino
authors.initials: M
authors.lastname: Montomoli
authors.affiliation: Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A Meyer Children's Hospital, University of Florence, Florence, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Pisano
authors.affiliation: Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A Meyer Children's Hospital, University of Florence, Florence, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Rosati
authors.affiliation: Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A Meyer Children's Hospital, University of Florence, Florence, Italy.
authors.forename: Renzo
authors.initials: R
authors.lastname: Guerrini
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D000483:Alleles; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D019295:Computational Biology / Q000379:methods; D004351:Drug Resistance / Q000235:genetics*; D004827:Epilepsy / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D058977:Molecular Sequence Annotation; D009154:Mutation; D010641:Phenotype; D017422:Sequence Analysis, DNA
chemical_list: D000927:Anticonvulsants
keywords: epilepsy; gene panel; mutation; next-generation sequencing