title: Molecular characterization of a cohort of 73 patients with infantile spasms syndrome.
abstract: Infantile Spasms syndrome (ISs) is a characterized by epileptic spasms occurring in clusters with an onset in the first year of life. West syndrome represents a subset of ISs that associates spasms in clusters, a hypsarrhythmia EEG pattern and a developmental arrest or regression. Aetiology of ISs is widely heterogeneous including many genetic causes. Many patients, however, remain without etiological diagnosis, which is critical for prognostic purpose and genetic counselling. In the present study, we performed genetic screening of 73 patients with different types of ISs by array-CGH and molecular analysis of 5 genes: CDKL5, STXBP1, KCNQ2, and GRIN2A, whose mutations cause different types of epileptic encephalopathies, including ISs, as well as MAGI2, which was suggested to be related to a subset of ISs. In total, we found a disease-causing mutation or CNV (Copy Number Variation) in 15% of the patients. These included 6 point mutations found in CDKL5 (n = 3) and STXBP1 (n = 3), 3 microdeletions (10 Mb in 2q24.3, 3.2 Mb in 5q14.3 including the region upstream to MEF2C, and 256 kb in 9q34 disrupting EHMT1), and 2 microduplications (671 kb in 2q24.3 encompassing SCN2A, and 11.93 Mb in Xq28). In addition, we discuss 3 CNVs as potential risk factors, including one 16p12.1 deletion, one intronic deletion of the NEDD4 gene, and one intronic deletion of CALN1 gene. The present findings highlight the efficacy of combined cytogenetic and targeted mutation screening to improve the diagnostic yield in patient with ISs.
authors.affiliation: Department of Molecular Genetics, Lyon University Hospital, Lyon, France; CRNL, CNRS UMR 5292, INSERM U1028, Lyon, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Boutry-Kryza
authors.affiliation: Department of Genetics, Lyon University Hospital, Lyon, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Labalme
authors.affiliation: Reference Center for Tuberous Sclerosis and Rare Epileptic Syndromes, Lyon University Hospital, Lyon, France.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Ville
authors.affiliation: Epilepsy, Sleep and Pediatric Neurophysiology Department, Lyon University Hospital, Lyon, France.
authors.forename: Julitta
authors.initials: J
authors.lastname: de Bellescize
authors.affiliation: Department of Genetics, Hospital Nord, Saint-Etienne University Hospital, France.
authors.forename: Renaud
authors.initials: R
authors.lastname: Touraine
authors.affiliation: Department of Genetics, Hospital Nord, Saint-Etienne University Hospital, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Prieur
authors.affiliation: CRNL, CNRS UMR 5292, INSERM U1028, Lyon, France; Department of Genetics, Lyon University Hospital, Lyon, France; Claude Bernard Lyon I University, Lyon, France.
authors.forename: Sarra
authors.initials: S
authors.lastname: Dimassi
authors.affiliation: Reference Center for Tuberous Sclerosis and Rare Epileptic Syndromes, Lyon University Hospital, Lyon, France.
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Poulat
authors.affiliation: Department of Genetics, Lyon University Hospital, Lyon, France.
authors.forename: Marianne
authors.initials: M
authors.lastname: Till
authors.affiliation: CRNL, CNRS UMR 5292, INSERM U1028, Lyon, France; Department of Genetics, Lyon University Hospital, Lyon, France.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Rossi
authors.affiliation: Pediatric Functional Exploration of the Nervous System Service, Hospital Nord, Amiens University Hospital, Amiens, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Bourel-Ponchel
authors.affiliation: Department of Neurology, Hospital Nord, Amiens University Hospital, Amiens, France.
authors.forename: Aline
authors.initials: A
authors.lastname: Delignières
authors.affiliation: Department of Neurology, Hospital Nord, Amiens University Hospital, Amiens, France.
authors.forename: Anne-Gaelle
authors.initials: AG
authors.lastname: Le Moing
authors.affiliation: Department of Pediatrics, Hospital Nord-Ouest, Villefranche sur Saone, France.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Rivier
authors.affiliation: Reference Center for Tuberous Sclerosis and Rare Epileptic Syndromes, Lyon University Hospital, Lyon, France; Claude Bernard Lyon I University, Lyon, France; CNRS UMR 5403, Institut des Sciences Cognitives, L2C2, Bron, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: des Portes
authors.affiliation: CRNL, CNRS UMR 5292, INSERM U1028, Lyon, France; Department of Genetics, Lyon University Hospital, Lyon, France; Claude Bernard Lyon I University, Lyon, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Edery
authors.affiliation: Department of Molecular Genetics, Lyon University Hospital, Lyon, France; Claude Bernard Lyon I University, Lyon, France; INSERM U1052, Lyon, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Calender
authors.affiliation: CRNL, CNRS UMR 5292, INSERM U1028, Lyon, France; Department of Genetics, Lyon University Hospital, Lyon, France; Claude Bernard Lyon I University, Lyon, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Sanlaville
authors.affiliation: CRNL, CNRS UMR 5292, INSERM U1028, Lyon, France; Department of Genetics, Lyon University Hospital, Lyon, France; Claude Bernard Lyon I University, Lyon, France. Electronic address: gaetan.lesca@chu-lyon.fr.
authors.forename: Gaetan
authors.initials: G
authors.lastname: Lesca
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002147:Calmodulin / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics; D005260:Female; D051528:Guanylate Kinases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006801:Humans; D007231:Infant, Newborn; D051658:KCNQ2 Potassium Channel / Q000235:genetics; D064326:MEF2 Transcription Factors / Q000235:genetics; D008297:Male; D051938:Munc18 Proteins / Q000235:genetics; D009154:Mutation; D062551:NAV1.2 Voltage-Gated Sodium Channel / Q000235:genetics; D000075702:Nedd4 Ubiquitin Protein Ligases; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics; D013036:Spasms, Infantile / Q000235:genetics*; D013577:Syndrome; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002147:Calmodulin; D002352:Carrier Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D051528:Guanylate Kinases; D011495:Histone-Lysine N-Methyltransferase; D051658:KCNQ2 Potassium Channel; D064326:MEF2 Transcription Factors; D051938:Munc18 Proteins; D062551:NAV1.2 Voltage-Gated Sodium Channel; D000075702:Nedd4 Ubiquitin Protein Ligases; D017346:Protein Serine-Threonine Kinases; D016194:Receptors, N-Methyl-D-Aspartate; D044767:Ubiquitin-Protein Ligases; C428830:CALN1 protein, human; C496914:KCNQ2 protein, human; C578040:MEF2C protein, human; C568251:SCN2A protein, human; C497937:STXBP1 protein, human; C455847:EHMT1 protein, human; C000618483:Nedd4 protein, human; C114482:CDKL5 protein, human; C485777:MAGI2 protein, human
keywords: CDKL5; Infantile spasms syndrome; MEF2C; SCN2A; STXBP1; West syndrome