title: Whole-exome sequencing improves the diagnosis yield in sporadic infantile spasm syndrome.
abstract: Infantile spasms syndrome (ISs) is characterized by clinical spasms with ictal electrodecrement, usually occurring before the age of 1 year and frequently associated with cognitive impairment. Etiology is widely heterogeneous, the cause remaining elusive in 40% of patients. We searched for de novo mutations in 10 probands with ISs and their parents using whole-exome sequencing (WES). Patients had neither consanguinity nor family history of epilepsy. Common causes of ISs were excluded by brain magnetic resonance imaging (MRI), metabolic screening, array-comparative genomic hybridization (CGH) and testing for mutations in CDKL5, STXBP1, and for ARX duplications. We found a probably pathogenic mutation in four patients. Missense mutations in SCN2A (p.Leu1342Pro) and KCNQ2 (p.Ala306Thr) were found in two patients with no history of epilepsy before the onset of ISs. The p.Asn107Ser missense mutation of ALG13 had been previously reported in four females with ISs. The fourth mutation was an in-frame deletion (p.Phe110del) in NR2F1, a gene whose mutations cause intellectual disability, epilepsy, and optic atrophy. In addition, we found a possibly pathogenic variant in KIF3C that encodes a kinesin expressed during neural development. Our results confirm that WES improves significantly the diagnosis yield in patients with sporadic ISs.
authors.affiliation: Department of Medical Genetics, Lyon University Hospital, Lyon, France.|CNRS UMR 5292, INSERM U1028, CNRL, Lyon, France.|Claude Bernard Lyon I University, University of Lyon, Lyon, France.|Cytogenetics and Reproductive Biology Department, Farhat Hached University Teaching Hospital, Sousse, Tunisia.|Common Service Units for Research in Genetics, Faculty of Medicine of Sousse, Avenue Mohamed Karoui, University of Sousse, Tunisia.
authors.forename: S
authors.initials: S
authors.lastname: Dimassi
authors.affiliation: Department of Medical Genetics, Lyon University Hospital, Lyon, France.
authors.forename: A
authors.initials: A
authors.lastname: Labalme
authors.affiliation: Department of Neuropediatrics, Lyon University Hospital, Lyon, France.
authors.forename: D
authors.initials: D
authors.lastname: Ville
authors.affiliation: Claude Bernard Lyon I University, University of Lyon, Lyon, France.|Department of Molecular Genetics, Lyon University Hospital, Lyon, France.
authors.forename: A
authors.initials: A
authors.lastname: Calender
authors.affiliation: Département de Génétique et Centre de Référence "Déficiences intellectuelles de causes rares", AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.|Department of Pediatric Neurophysiology, Amiens University Hospital, Amiens, France.
authors.forename: C
authors.initials: C
authors.lastname: Mignot
authors.affiliation: CNRS UMR 5292, INSERM U1028, CNRL, Lyon, France.|Claude Bernard Lyon I University, University of Lyon, Lyon, France.|Department of Molecular Genetics, Lyon University Hospital, Lyon, France.
authors.forename: N
authors.initials: N
authors.lastname: Boutry-Kryza
authors.affiliation: Epilepsy, Sleep and Pediatric Neurophysiology Department, Lyon University Hospital, Lyon, France.
authors.forename: J
authors.initials: J
authors.lastname: de Bellescize
authors.affiliation: Department of Pediatrics, Nord-Ouest Hospital, Villefranche-sur-Saone, France.
authors.forename: C
authors.initials: C
authors.lastname: Rivier-Ringenbach
authors.affiliation: Department of Pediatric Neurophysiology, Amiens University Hospital, Amiens, France.
authors.forename: E
authors.initials: E
authors.lastname: Bourel-Ponchel
authors.affiliation: Claude Bernard Lyon I University, University of Lyon, Lyon, France.|Service des Maladies Héréditaires du métabolisme, INSERM U1060, Lyon University Hospital, Lyon, France.
authors.forename: D
authors.initials: D
authors.lastname: Cheillan
authors.affiliation: Department of Cell Biotechnology, ENS Lyon, Lyon University Hospital, Lyon, France.
authors.forename: T
authors.initials: T
authors.lastname: Simonet
authors.affiliation: Department of Pediatric Neurology, Hôpital Trousseau, Assistance Publique des Hôpitaux de Paris, Paris, France.
authors.forename: K
authors.initials: K
authors.lastname: Maincent
authors.affiliation: Department of Medical Genetics, Lyon University Hospital, Lyon, France.|CNRS UMR 5292, INSERM U1028, CNRL, Lyon, France.
authors.forename: M
authors.initials: M
authors.lastname: Rossi
authors.affiliation: Department of Medical Genetics, Lyon University Hospital, Lyon, France.
authors.forename: M
authors.initials: M
authors.lastname: Till
authors.affiliation: Cytogenetics and Reproductive Biology Department, Farhat Hached University Teaching Hospital, Sousse, Tunisia.|Common Service Units for Research in Genetics, Faculty of Medicine of Sousse, Avenue Mohamed Karoui, University of Sousse, Tunisia.
authors.forename: S
authors.initials: S
authors.lastname: Mougou-Zerelli
authors.affiliation: Department of Medical Genetics, Lyon University Hospital, Lyon, France.|CNRS UMR 5292, INSERM U1028, CNRL, Lyon, France.|Claude Bernard Lyon I University, University of Lyon, Lyon, France.
authors.forename: P
authors.initials: P
authors.lastname: Edery
authors.affiliation: Cytogenetics and Reproductive Biology Department, Farhat Hached University Teaching Hospital, Sousse, Tunisia.|Common Service Units for Research in Genetics, Faculty of Medicine of Sousse, Avenue Mohamed Karoui, University of Sousse, Tunisia.
authors.forename: A
authors.initials: A
authors.lastname: Saad
authors.affiliation: Département de Génétique et Centre de Référence "Déficiences intellectuelles de causes rares", AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.|GRC-Génétique des Déficiences Intellectuelles de Causes rares, Université Pierre et Marie Curie, Paris, France.
authors.forename: D
authors.initials: D
authors.lastname: Heron
authors.affiliation: Department of Neuropediatrics, Lyon University Hospital, Lyon, France.|Department of Molecular Genetics, Lyon University Hospital, Lyon, France.|Reference Center for Tuberous Sclerosis and Rare Epileptic Syndromes, Lyon University Hospital, Lyon, France.
authors.forename: V
authors.initials: V
authors.lastname: des Portes
authors.affiliation: Department of Medical Genetics, Lyon University Hospital, Lyon, France.|CNRS UMR 5292, INSERM U1028, CNRL, Lyon, France.|Claude Bernard Lyon I University, University of Lyon, Lyon, France.
authors.forename: D
authors.initials: D
authors.lastname: Sanlaville
authors.affiliation: Department of Medical Genetics, Lyon University Hospital, Lyon, France.|CNRS UMR 5292, INSERM U1028, CNRL, Lyon, France.|Claude Bernard Lyon I University, University of Lyon, Lyon, France.
authors.forename: G
authors.initials: G
authors.lastname: Lesca
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D017124:Conserved Sequence; D059472:Exome / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D011247:Pregnancy; D017422:Sequence Analysis, DNA; D013036:Spasms, Infantile / Q000175:diagnosis* / Q000235:genetics*; D013577:Syndrome
keywords: ALG13; KCNQ2; KIF3C; NR2F1; SCN2A; infantile spasms; whole-exome sequencing