Title :

Molecular and Phenotypic Characterization of the <i>RORB</i>-Related Disorder.

Author(s) :

Gokce-Samar, Z. [Auteur]
Vetro, A. [Auteur]
De Bellescize, J. [Auteur]
Pisano, T. [Auteur]
Monteiro, Laloa [Auteur]
Penaud, Noémie [Auteur]
Korff, Christian M. [Auteur]
Fluss, Joel [Auteur]
Marini, C. [Auteur]
Cesaroni, E. [Auteur]
Alvarez, B. M. [Auteur]
Sanlaville, Damien [Auteur]
Université Claude Bernard Lyon 1 [UCBL]
Institut NeuroMyoGène [INMG]
Chatron, N. [Auteur]
Arzimanoglou, A. A. [Auteur]
Labalme, A. [Auteur]
Cuddapah, V. A. [Auteur]
Ruggiero, S. M. [Auteur]
Lecoquierre, François [Auteur]
Cancer and Brain Genomics [CBG]
Université de Rouen Normandie [UNIROUEN]
Nicolas, G. [Auteur]
Marie, G. A. [Auteur]
Lebas, A. [Auteur]
Testard, H. O. [Auteur]
Helbig, K. L. [Auteur]
Ruiz, A. [Auteur]
Ngoh, A. [Auteur]
Kurian, M. A. [Auteur]
Reid, K. [Auteur]
Spaull, R. [Auteur]
Joset, P. [Auteur]
Ramantani, G. [Auteur]
Steindl, K. [Auteur]
Krenn, M. [Auteur]
Gerstl, L. [Auteur]
Vieker, S. [Auteur]
Craiu, D. [Auteur]
Pendziwiat, M. [Auteur]
Haldeman-Englert, C. [Auteur]
Kanivets, I. [Auteur]
Romanova, I. [Auteur]
Rajan, D. S. [Auteur]
Rosenfeld, J. A. [Auteur]
Au, M. [Auteur]
Grand, K. [Auteur]
Graham, M. [Auteur]
Isapof, A. [Auteur]
Villeneuve, N. [Auteur]
Smol, Thomas [Auteur]
Maladies Rares du Développement : Génétique, Régulation et Protéomique (RADEME) - ULR 7364
Caumes, R. [Auteur]
Zacher, P. [Auteur]
Neuser, S. [Auteur]
Tinschert, S. [Auteur]
Platzer, K. [Auteur]
Bartolomaeus, T. [Auteur]
Mohnke, I. [Auteur]
Radtke, M. [Auteur]
Jamra, R. A. [Auteur]
Helbig, I. [Auteur]
Jansen, F. E. [Auteur]
Koop, K. [Auteur]
Rudolf, G. [Auteur]
Küry, S. [Auteur]
Courchet, J. [Auteur]
Guerrini, R. [Auteur]
Lesca, G. [Auteur]

Journal title :

Neurology

Abbreviated title :

Neurology

Volume number :

102

Pages :

e207945

Publication date :

2024-01-10

ISSN :

1526-632X

HAL domain(s) :

Sciences du Vivant [q-bio]

English abstract : [en]

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 ...
Show more >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.Show less >

Peer reviewed article :

Oui

Audience :

Internationale

Popular science :

Non

European Project :

ITHACA

ANR Project :

Construction, Fonction Cognitive et Réhabilitation du Cerveau
PROJET AVENIR LYON SAINT-ETIENNE

Administrative institution(s) :

Université de Lille
CHU Lille

Collections :

• Maladies Rares du Développement : Génétique, Régulation et Protéomique (RADEME) - ULR 7364

Submission date :

2024-05-15T21:58:32Z
2024-07-01T15:16:53Z