Talarico Mariagrazia, de Bellescize Julitta, De Wachter Matthias, Le Guillou Xavier, Le Meur Guylène, Egloff Matthieu, Isidor Bertrand, Cogné Benjamin, Beysen Diane, Rollier Paul, Fradin Melanie, Pasquier Laurent, Guella Ilaria, Hickey Scott E, Benke Paul J, Shillington Amelle, Kumps Candy, Vanakker Olivier, Gerkes Erica H, Lakhani Shenela, Romanova Irina, Kanivets Ilya, Brugger Melanie, Vill Katharina, Caylor Raymond C, Skinner Cindy, Tinker Rory J, Stödberg Tommy, Nümann Astrid, Haack Tobias B, Deininger Natalie, Hengel Holger, Jury Jeanne, Conrad Solène, Mercier Sandra, Yoon Grace, Tsuboyama Melissa, Barcia Giulia, Gitiaux Cyril, Rio Marlène, Bevot Andrea, Redon Sylvia, Uguen Kevin, Wonneberger Antje, Schulz Alexander, Timmann Dagmar, Karlowicz Danielle Hays, Chatron Nicolas, Carnevale Amanda, Mahida Sonal, Õunap Katrin, Kury Sébastien, Cabet Sara, Lesca Gaetan
Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy; Genetics Department, Hospices Civils de Lyon, Member of the ERN EpiCARE, Lyon, France; Neuromyogene Institute, Pathology and Genetics of neuron and muscle, CNRS UMR 5261 INSERM U1315, University of Lyon-Université Claude Bernard Lyon 1, Lyon, France.
Department of Clinical Epileptology, Sleep Disorders and Functional Neurology in Children, University Hospital of Lyon (HCL), Member of the ERN EpiCARE, Lyon, France.
Genet Med. 2025 Apr;27(4):101347. doi: 10.1016/j.gim.2024.101347. Epub 2024 Dec 17.
RORA encodes the RAR-related orphan receptor-α, playing a pivotal role in cerebellar maturation and function. Here, we report the largest series of individuals with RORA-related-neurodevelopmental disorder.
Forty individuals (30 unrelated; 10 siblings from 4 families) carrying RORA pathogenic/likely pathogenic variants were collected through an international collaboration.
The 33 variants (29 de novo, 4 inherited, and 1 shared), identified by genome/exome sequencing (n = 21), chromosomal microarray analysis (n = 7), or gene panels (n = 4), included frameshift (n = 18/33), missense (n = 9/33), and stop codon (n = 6/33). Developmental disability (n = 32/37), intellectual disability (n = 22/32), and cerebellar signs (n = 25/34) were the most striking clinical features. Cerebellar symptoms were divided into early-onset, late-onset, and progressive subgroups. Cerebellar hypoplasia, atrophy, or both (n = 16/25) were more frequent in individuals with missense variants in the DNA-binding domain. Epilepsy (n = 18/38), with prominent myoclonic seizure types (n = 11/18), was classified in (1) genetic generalized epilepsy (n = 10/18) with a syndromic diagnosis identifiable for 6: epilepsy with eyelid myoclonia (n = 5/6) and epilepsy with myoclonic absence (n = 1/6); (2) developmental and epileptic encephalopathy (n = 5/18); and (3) unclassified (n = 3/18). A participant with rapid deterioration of visual acuity and cone/rod dystrophy was reported.
Missense variants in DNA-binding domain correlate to a more severe cerebellar phenotype. The RORA-related-neurodevelopmental disorder triad comprises developmental disability, cerebellar features, and a spectrum of myoclonic epilepsy.
RORA编码视黄酸受体相关孤儿受体α，在小脑成熟和功能中起关键作用。在此，我们报告了最大系列的与RORA相关的神经发育障碍患者。
通过国际合作收集了40名携带RORA致病/可能致病变异的个体（30名无亲缘关系；4个家庭的10名兄弟姐妹）。
通过基因组/外显子组测序（n = 21）、染色体微阵列分析（n = 7）或基因检测板（n = 4）鉴定出33种变异（29种新发、4种遗传和1种共享），包括移码突变（n = 18/33）、错义突变（n = 9/33）和终止密码子突变（n = 6/33）。发育障碍（n = 32/37）、智力障碍（n = 22/32）和小脑体征（n = 25/34）是最显著的临床特征。小脑症状分为早发型、晚发型和进行性亚组。DNA结合域错义突变的个体中，小脑发育不全、萎缩或两者皆有（n = 16/25）更为常见。癫痫（n = 18/38），以明显的肌阵挛发作类型为主（n = 11/18），分为：（1）遗传性全身性癫痫（n = 10/18），其中6例有可识别的综合征诊断：眼睑肌阵挛癫痫（n = 5/6）和肌阵挛失神癫痫（n = 1/6）；（2）发育性和癫痫性脑病（n = 5/18）；（3）未分类（n = 3/18）。报告了一名视力快速恶化并伴有视锥/视杆营养不良的参与者。
DNA结合域的错义突变与更严重的小脑表型相关。与RORA相关的神经发育障碍三联征包括发育障碍、小脑特征和一系列肌阵挛癫痫。
