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SCN1A duplications and deletions detected in Dravet syndrome: Implications for molecular diagnosis |
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| Authors: | Carla Marini Ingrid E. Scheffer Rima Nabbout Davide Mei Kathy Cox Leanne M. Dibbens Jacinta M. McMahon Xenia Iona Rochio Sanchez Carpintero Maurizio Elia Maria Roberta Cilio Nicola Specchio Lucio Giordano Pasquale Striano Elena Gennaro J. Helen Cross Sara Kivity Miriam Y. Neufeld Zaid Afawi Eva Andermann Daniel Keene Olivier Dulac Federico Zara Samuel F. Berkovic Renzo Guerrini John C. Mulley |
| Affiliation: | Child Neurology Unit, Children's Hospital A. Meyer, University of Florence, Florence, Italy;;Department of Medicine (Neurology), University of Melbourne and Austin Health, Heidelberg, Australia;;Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Australia;;Service de Neurologie Pédiatrique, AP-HP, Hopital Necker-Enfants Malades, Centre de Référence Épilepsies Rares, Paris, France;;Department of Genetic Medicine, Women's and Children's Hospital, Adelaide, Australia;;School of Pediatrics and Reproductive Health, University of Adelaide, Adelaide, Australia;;Paediatric Neurology Unit, Department of Paediatrics, Clinica Universitaria de Navarra, University of Navarra, Pamplona, Spain;;Department of Neurology, Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), Troina, Enna, Italy;;Division of Neurology, Bambino Gesu Children's Hospital, Roma, Italy;;Department of Child and Adolescent Neurology and Psychiatry, Spedali Civili, Brescia, Italy;;Muscular and Neurodegenerative Disease Unit, Institute G. Gaslini, University of Genova, Genova, Italy;;Laboratory of Genetics, E.O. Ospedale Galliera, Genova, Italy;;UCL Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom;;Schneider Children's Medical Center, Petaq Tikva, Israel;;Department of Neurology, Tel Aviv Sourasky Medical Centre, Tel Aviv, Israel;;Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada;;Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada;;School of Molecular and Biomedical Sciences, University of Adelaide, Adelaide, Australia |
| Abstract: | Objective: We aimed to determine the type, frequency, and size of microchromosomal copy number variations (CNVs) affecting the neuronal sodium channel α 1 subunit gene ( SCN1A ) in Dravet syndrome (DS), other epileptic encephalopathies, and generalized epilepsy with febrile seizures plus (GEFS+). Methods: Multiplex ligation-dependent probe amplification (MLPA) was applied to detect SCN1A CNVs among 289 cases (126 DS, 97 GEFS+, and 66 with other phenotypes). CNVs extending beyond SCN1A were further characterized by comparative genome hybridization (array CGH). Results: Novel SCN1A CNVs were found in 12.5% of DS patients where sequence-based mutations had been excluded. We identified the first partial SCN1A duplications in two siblings with typical DS and in a patient with early-onset symptomatic generalized epilepsy. In addition, a patient with DS had a partial SCN1A amplification of 5–6 copies. The remaining CNVs abnormalities were four partial and nine whole SCN1A deletions involving contiguous genes. Two CNVs (a partial SCN1A deletion and a duplication) were inherited from a parent, in whom there was mosaicism. Array CGH showed intragenic deletions of 90 kb and larger, with the largest of 9.3 Mb deleting 49 contiguous genes and extending beyond SCN1A. Discussion: Duplication and amplification involving SCN1A are now added to molecular mechanisms of DS patients. Our findings showed that 12.5% of DS patients who are mutation negative have MLPA-detected SCN1A CNVs with an overall frequency of about 2–3%. MLPA is the established second-line testing strategy to reliably detect all CNVs of SCN1A from the megabase range down to one exon. Large CNVs extending outside SCN1A and involving contiguous genes can be precisely characterized by array CGH. |
| Keywords: | Array CGH Deletion Dravet syndrome Duplication Early-onset severe epilepsy Multiplex ligation-dependent probe amplification SCN1A |