- 相关障碍的分子和表型特征。
Molecular and Phenotypic Characterization of the -Related Disorder.
机构信息
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 University of Florence, Italy; Univ Lyon (L.M., N.P., D.S., N.C., J.C., G.L.), Univ Lyon 1, CNRS, INSERM, Physiopathologie et Génétique du Neurone et du Muscle, UMR5261, U1315, Institut NeuroMyoGène, France; Pediatric Neurology Unit (C.M.K., J.F.), University Hospitals of Geneva, Switzerland; Child Neurology and Psychiatric Unit (C.M., E.C.), Children's Hospital G. Salesi, Azienda Universitaria Ospedaliera delle Marche, Ancona, Italy; Department of Neurology (B.M.A.), University Hospitals of Montpellier; Department of Genetics (D.S., N.C., A. Labalme, G.L.), University Hospitals of Lyon, HCL, Member of ERN Epicare, France; Paediatric Epilepsy Research (A.A.A.), Child Neurology Department, Member of the ERN EpiCARE, San Juan de Dios Children's Hospital, Barcelona, Spain; Division of Neurology (V.A.C., S.M.R., I.H.), and The Epilepsy NeuroGenetics Initiative (ENGIN) (V.A.C., S.M.R., K.L.H., I.H.), Children's Hospital of Philadelphia, PA; Department of Neurology (V.A.C., S.M.R., I.H.), University of Pennsylvania Perelman School of Medicine, Philadelphia; Univ Rouen Normandie (F.L., G.N.), Inserm U1245 and CHU Rouen, Department of Genetics and Reference Center for Developmental Disorders; Department of Pediatric Neurology (G.A.M., A. Lebas), University Hospitals of Rouen; Department of Pediatric Neurology (H.O.T.), Hospital of Alpes Léman, Annemasse, France; Department of Pediatric Neurology (A.R.), Barcelona Children's Hospital, University of Barcelona, Spain; Developmental Neurosciences (A.N., M.A.K., K.R., R.S.), Zayed Centre for Research, University College of London, Great Ormond Street Hospital, Institute of Child Health, United Kingdom; Institute of Medical Genetics (P.J.), University of Zürich; Department of Neuropediatrics (G. Ramantani, K.S.), University Children's Hospital and University of Zürich, Switzerland; Department of Neurology (M.K.), Medical University of Vienna, Austria; Division of Pediatric Neurology, Developmental Medicine and Social Pediatrics (L.G.), Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany; Institute of Human Genetics (S.V.), Medical University of Innsbruck, Innsbruck, Austria; Werner-Forßmann-Krankenhaus (S.V., S.T.), Eberswalde, Germany; Pediatric Neurology Discipline (D.C.), Neurosciences Department, Carol Davila University of Medicine Bucharest; Pediatric Neurology Clinic (D.C.), Al Obregia Hospital, Center of Expertise for Pediatric Neurology Rare Disorders, Member of ERN EpiCARE, Bucharest, Romania; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel, Germany; Mission Fullerton Genetics Center (C.H.-E.), Asheville, NC; Department of Neurology (I.K.), Svt. Luka's Institute of Child Neurology and Epilepsy, Moscow; Department of Medical Genetics (I.R.), Kazan State University, Russia; Division of Child Neurology (D.S.R.), Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, PA; Department of Molecular and Human Genetics (J.A.R.), Baylor College of Medicine, Houston, TX; Division of Clinical Genetics and Dysmorphology (M.A., K.G., J.M.G.), Cedars-Sinai Medical Center, Los Angeles, CA; Department of Neurology (A.I.), University Hospitals of Armand Trousseau, AP-HP, Paris; Department of Pediatric Neurology (N.V.), University Hospitals of Marseille, AP-HM; Univ. Lille (T.S.), CHU Lille, ULR7364, RADEME, Institute of Medical Genetics; Department of Clinical Genetics (R.C.), CHU Lille, France; Institute of Human Genetics (P.Z., S.N., K.P., T.B., I.M., M.R., R.A.J.), University of Leipzig Medical Center, Germany; Institute of Human Genetics (S.T.), Medical University of Innsbruck, Austria; Department of Biomedical and Health Informatics (DBHi) (I.H.), Children's Hospital of Philadelphia, PA; Department of Pediatric Neurology (F.E.J., K.K.), Brain Center UMC Utrecht, Member of ERN Epicare, Utrecht, the Netherlands; Department of Neurology (G. Rudolf), Strasbourg University Hospital; and Nantes Université (S.K.), CHU Nantes, Service de Génétique Médicale, and CNRS, INSERM, l'institut du thorax, France.
出版信息
Neurology. 2024 Jan 23;102(2):e207945. doi: 10.1212/WNL.0000000000207945. Epub 2023 Dec 22.
BACKGROUND AND OBJECTIVES
Heterozygous variants in RAR-related orphan receptor B () 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 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 . 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 , 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 -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.
背景和目的
最近，RAR 相关孤儿受体 B（）中的杂合变体与特发性全身性癫痫的易感性有关。然而，迄今为止，描述该基因在癫痫伴智力障碍（ID）患者中的致病性变体的报道很少。在这项研究中，我们旨在描绘与致病性变体相关的癫痫表型，并提供支持变体致病性的论据。
方法
通过国际合作，我们分析了一组携带杂合变体的患者的发作特征、脑电图数据和基因型。为了深入了解疾病机制，我们对 5 种选定变体（2 种截断和 3 种错义）的小鼠胚胎进行了皮质电穿孔，并评估了表达和定量的轴突形态变化。
结果
我们确定了 35 名患者（17 名男性，中位年龄 10 岁，范围 2.5-23 岁）携带 32 种不同的杂合变体，包括 28 种单核苷酸变体或小插入/缺失（12 种错义，12 种移码或无义，2 种剪接位点变体，2 种框内缺失），和 4 种微缺失；18 例为新生突变，10 例为遗传突变。35 名患者中有 31 名（89%）报告有癫痫发作，中位发病年龄为 3 岁（范围 4 个月-12 岁）。25 名癫痫患者出现失神发作（81%）。19 名患者经历了单一的发作类型：失神、肌阵挛失神或失神伴眼睑肌阵挛和局灶性发作。9 名患者失神发作伴有其他全身性发作类型。1 名患者出现失神发作伴光敏性枕叶发作。其他 3 名患者出现全身性强直阵挛发作而无失神发作。85%的患者存在不同程度的智力障碍。在培养的神经元中进行的表达研究表明，5 种测试变体（截断和错义变体）的轴突较短，支持蛋白功能受损。
讨论
在大多数患者中，与相关疾病的表型关联是失神发作伴轻度至中度 ID。我们对本队列中的变体进行了计算机模拟和体外评估，包括在培养神经元中进行轴突形态发生实验，支持其致病性，显示出低功能效应。
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