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Molecular and Phenotypic Characterization of the RORB-Related Disorder.
Gokce-Samar, Zeynep; Vetro, Annalisa; De Bellescize, Julitta; Pisano, Tiziana; Monteiro, Laloe; Penaud, Noémie; Korff, Christian M; Fluss, Joel; Marini, Carla; Cesaroni, Elisabetta; Alvarez, Blanca Mercedes; Sanlaville, Damien; Chatron, Nicolas; Arzimanoglou, Alexis A; Labalme, Audrey; Cuddapah, Vishnu A; Ruggiero, Sarah M; Lecoquierre, Francois; Nicolas, Gael; Marie, Guerrot Anne; Lebas, Axel; Testard, Herve O; Helbig, Katherine L; Ruiz, Anna; Ngoh, Adeline; Kurian, Manju A; Reid, Kimberley; Spaull, Robert; Joset, Pascal; Ramantani, Georgia; Steindl, Katharina; Krenn, Martin; Gerstl, Lucia; Vieker, Silvia; Craiu, Dana; Pendziwiat, Manuela; Haldeman-Englert, Chad; Kanivets, Ilya; Romanova, Irina; Rajan, Deepa S; Rosenfeld, Jill A; Au, Margaret; Grand, Katheryn; Graham, John; Isapof, Arnaud; Villeneuve, Nathalie; Smol, Thomas; Caumes, Roseline; Zacher, Pia; Neuser, Sonja.
Afiliação
  • Gokce-Samar Z; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Vetro A; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • De Bellescize J; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Pisano T; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Monteiro L; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Penaud N; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Korff CM; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Fluss J; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Marini C; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Cesaroni E; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Alvarez BM; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Sanlaville D; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Chatron N; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Arzimanoglou AA; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Labalme A; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Cuddapah VA; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Ruggiero SM; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Lecoquierre F; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Nicolas G; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Marie GA; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Lebas A; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Testard HO; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Helbig KL; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Ruiz A; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Ngoh A; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Kurian MA; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Reid K; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Spaull R; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Joset P; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Ramantani G; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Steindl K; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Krenn M; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Gerstl L; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Vieker S; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Craiu D; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Pendziwiat M; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Haldeman-Englert C; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Kanivets I; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Romanova I; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Rajan DS; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Rosenfeld JA; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Au M; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Grand K; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Graham M; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Isapof A; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Villeneuve N; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Smol T; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Caumes R; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Zacher P; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
  • Neuser S; From the Department of Pediatric Clinical Epileptology (Z.G.-S., J.D.B., A.A.A.), Sleep Disorders and Functional Neurology, University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Neuroscience Department (A.V., T.P., R.G.) IRCCS, Children's Hospital Meyer, Member of ERN Epicare, and Univer
Neurology ; 102(2): e207945, 2024 01 23.
Article em En | MEDLINE | ID: mdl-38165337
ABSTRACT
BACKGROUND AND

OBJECTIVES:

Heterozygous variants in RAR-related orphan receptor B (RORB) have recently been associated with susceptibility to idiopathic generalized epilepsy. However, few reports have been published so far describing pathogenic variants of this gene in patients with epilepsy and intellectual disability (ID). In this study, we aimed to delineate the epilepsy phenotype associated with RORB pathogenic variants and to provide arguments in favor of the pathogenicity of variants.

METHODS:

Through an international collaboration, we analyzed seizure characteristics, EEG data, and genotypes of a cohort of patients with heterozygous variants in RORB. To gain insight into disease mechanisms, we performed ex vivo cortical electroporation in mouse embryos of 5 selected variants, 2 truncating and 3 missense, and evaluated on expression and quantified changes in axonal morphology.

RESULTS:

We identified 35 patients (17 male, median age 10 years, range 2.5-23 years) carrying 32 different heterozygous variants in RORB, including 28 single-nucleotide variants or small insertions/deletions (12 missense, 12 frameshift or nonsense, 2 splice-site variants, and 2 in-frame deletions), and 4 microdeletions; de novo in 18 patients and inherited in 10. Seizures were reported in 31/35 (89%) patients, with a median age at onset of 3 years (range 4 months-12 years). Absence seizures occurred in 25 patients with epilepsy (81%). Nineteen patients experienced a single seizure type absences, myoclonic absences, or absences with eyelid myoclonia and focal seizures. Nine patients had absence seizures combined with other generalized seizure types. One patient had presented with absences associated with photosensitive occipital seizures. Three other patients had generalized tonic-clonic seizures without absences. ID of variable degree was observed in 85% of the patients. Expression studies in cultured neurons showed shorter axons for the 5 tested variants, both truncating and missense variants, supporting an impaired protein function.

DISCUSSION:

In most patients, the phenotype of the RORB-related disorder associates absence seizures with mild-to-moderate ID. In silico and in vitro evaluation of the variants in our cohort, including axonal morphogenetic experiments in cultured neurons, supports their pathogenicity, showing a hypomorphic effect.
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Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Epilepsia Generalizada / Epilepsia Tipo Ausência / Deficiência Intelectual Tipo de estudo: Prognostic_studies Limite: Adolescent / Adult / Animals / Child / Child, preschool / Humans / Infant / Male Idioma: En Revista: Neurology Ano de publicação: 2024 Tipo de documento: Article
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Epilepsia Generalizada / Epilepsia Tipo Ausência / Deficiência Intelectual Tipo de estudo: Prognostic_studies Limite: Adolescent / Adult / Animals / Child / Child, preschool / Humans / Infant / Male Idioma: En Revista: Neurology Ano de publicação: 2024 Tipo de documento: Article