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

• Published in: Human mutation Vol. 38; no. 2; pp. 216 - 225
• Main Authors: Parrini, Elena, Marini, Carla, Mei, Davide, Galuppi, Anna, Cellini, Elena, Pucatti, Daniela, Chiti, Laura, Rutigliano, Domenico, Bianchini, Claudia, Virdò, Simona, Vita, Dalila, Bigoni, Stefania, Barba, Carmen, Mari, Francesco, Montomoli, Martino, Pisano, Tiziana, Rosati, Anna, Guerrini, Renzo
• Format: Journal Article
• Language: English
• Published: United States Hindawi Limited 01.02.2017
• Subjects: Adolescent; Age of Onset; Alleles; Anticonvulsants - pharmacology; Anticonvulsants - therapeutic use; Child; Child, Preschool; Computational Biology - methods; Drug resistance; Drug Resistance - genetics; Epilepsy; Epilepsy - diagnosis; Epilepsy - drug therapy; Epilepsy - genetics; Female; Gene Expression Profiling; gene panel; Genes; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Infant; Infant, Newborn; Magnetic Resonance Imaging - methods; Male; Molecular Sequence Annotation; Mutation; next‐generation sequencing; Pediatrics; Phenotype; Sequence Analysis, DNA; epilepsy; mutation; next-generation sequencing; gene panel
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/humu.23149

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. Next Generation Sequencing (NGS) gene panels represent a cost‐effective diagnostic option in pediatric drug‐resistant epilepsies. Carefully and frequently updated gene panels, comprehensive of both well‐known and rare epilepsy associated genes, enable molecular diagnosis of atypical phenotypes, broadening genotype‐phenotype correlations. Using NGS gene panels in the clinical diagnostic setting helps clinicians improving management, avoiding numerous investigations including invasive procedures, prognostication, guiding treatment choices in some cases, and providing appropriate genetic counselling to families.