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

Domenica Immacolata Battaglia, Elena Parrini, Carla Marini, Davide Mei, Anna Galuppi, Elena Cellini, Daniela Pucatti, Laura Chiti, Domenico Rutigliano, Claudia Bianchini, Simona Virdò, Dalila De Vita, Stefania Bigoni, Carmen Barba, Francesco Mari, Martino Montomoli, Tiziana Pisano, Anna Rosati, Renzo Guerrini, Patrizia AccorsiAnna Ardissone, Gianna Bertani, Gabriella Borgarello, Elisabetta Cesaroni, Sara Chiari, Duccio Maria Cordelli, Viola Doccini, Ilaria Donati, Elena Fontana, Carlo Fusco, Mattia Gentile, Lucio Giordano, Sandra Jacinto, Vincenzo Leuzzi, Salvatore Mangano, Mario Mastrangelo, Federico Melani, Laure Obino, Chiara Offer, Dario Pruna, Francesca Ragona, Paolo Ricciardelli, Michela Salandin, Antonino Saporoso, Federico Sicca, Nicola Specchio, Katalin Sterebova

Risultato della ricerca: Contributo in rivistaArticolo in rivista

79 Citazioni (Scopus)

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.
Lingua originaleEnglish
pagine (da-a)216-225
Numero di pagine10
RivistaHuman Mutation
Volume38
DOI
Stato di pubblicazionePubblicato - 2017

Keywords

  • Adolescent
  • Age of Onset
  • Alleles
  • Anticonvulsants
  • Child
  • Child, Preschool
  • Computational Biology
  • Drug Resistance
  • Epilepsy
  • Female
  • Gene Expression Profiling
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Infant
  • Infant, Newborn
  • Magnetic Resonance Imaging
  • Male
  • Molecular Sequence Annotation
  • Mutation
  • Phenotype
  • Sequence Analysis, DNA
  • epilepsy
  • gene panel
  • mutation
  • next-generation sequencing

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