RORA-neurodevelopmental disorder: A unique triad of developmental disabilities, cerebellar anomalies, and myoclonic seizures
2 PGNM - Physiopathologie et génétique du neurone et du muscle / Pathophysiology and Genetics of Neuron and Muscle
3 HCL - Hospices Civils de Lyon
4 UZA - Antwerp University Hospital [Edegem]
5 Service de Génétique [CHU Poitiers]
6 LNEC [Poitiers] - Laboratoire de neurosciences expérimentales et cliniques [U 1084]
7 TARGET - Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques / Translational Research in Gene Therapy - UMR_S 1089
8 ITX-lab - ITX-lab unité de recherche de l'institut du thorax UMR1087 UMR6291
9 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Pontchaillou]
10 UBC - University of British Columbia [Canada]
11 OSU - The Ohio State University [Columbus]
12 Cincinnati Children's Hospital Medical Center
13 Ghent University Hospital
14 UMCG - University Medical Center Groningen [Groningen]
15 KPFU - Kazan State University
16 Université technique de Munich, Département de physique = Technical University of Munich. Department of Physics = Technische Universität München. Physik-Department [Garching]
17 University Hospital LMU Munich
18 The Greenwood Genetic Center
19 Vanderbilt University Medical Center [Nashville]
20 Karolinska University Hospital [Stockholm]
21 Charité - UniversitätsMedizin = Berlin University Medicine
22 Eberhard Karls Universität Tübingen = University of Tübingen
23 University of Toronto
24 Boston Children's Hospital
25 Hôpital Necker - Enfants Malades [AP-HP]
26 Universitätsklinikum Tübingen = University Hospital of Tuebingen
27 GGB - Génétique, génomique fonctionnelle et biotechnologies (UMR 1078)
28 Universitätsklinikum Jena = Jena University Hospital [Jena, Germany]
29 AöR - University Hospital Essen
30 Duke University Medical Center
31 Tartu Ülikool = University of Tartu [Estonie]
- Fonction : Auteur
- PersonId : 1307399
- IdHAL : xavier-le-guillou-horn
- ORCID : 0000-0001-9350-8177
- IdRef : 25355604X
- Fonction : Auteur
- PersonId : 1359502
- IdHAL : megloff
- ORCID : 0000-0002-3146-1622
- IdRef : 220113645
- Fonction : Auteur
- PersonId : 1271347
- IdHAL : paul-jg-rollier
- ORCID : 0000-0001-7303-8825
- Fonction : Auteur
- Fonction : Auteur
- Fonction : Auteur
- Fonction : Auteur
- PersonId : 1382108
- ORCID : 0000-0001-7310-1142
- Fonction : Auteur
- PersonId : 769268
- ORCID : 0000-0001-7691-9492
- IdRef : 124685811
Résumé
Purpose: 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. Methods: Forty individuals (30 unrelated; 10 siblings from 4 families) carrying RORA pathogenic/likely pathogenic variants were collected through an international collaboration. Results: 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. Conclusion: 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.
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