Molecular and Phenotypic Characterization of the RORB-Related Disorder.
Обработка статьи · этапы, ошибки и управление
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
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, Tinschert Sigrid, Platzer Konrad, Bartolomaeus Tobias, Mohnke Ines, Radtke Maximilian, Jamra Rami Abou, Helbig Ingo, Jansen Floortje E, Koop Klaas, Rudolf Gabrielle, Küry Sebastien, Courchet Julien, Guerrini Renzo, Lesca Gaetan
Аннотация
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.