RORA-neurodevelopmental disorder: A unique triad of developmental disabilities, cerebellar anomalies, and myoclonic seizures

• DOI: 10.1016/j.gim.2024.101347
• Publication Date: 2024-12-17T16:35:28Z
• Authors: Mariagrazia Talarico; Julitta de Belles...; Matthias De Wachter; Xavier Le Guillou; Guylène Le Meur; Matthieu Egloff; Bertrand Isidor; Benjamin Cogné; Diane Beysen; Paul Rollier; Melanie Fradin; Laurent Pasquier; Ilaria Guella; Scott E. Hickey; Paul J. Benke; Amelle Shillington; Candy Kumps; Olivier Vanakker; Erica H. Gerkes; Shenela Lakhani; Irina Romanova; Ilya Kanivets; Melanie Brugger; Katharina Vill; Raymond C. Caylor; Cindy Skinner; Rory J. Tinker; Tommy Stödberg; Astrid Nümann; Tobias B. Haack; Natalie Deininger; Holger Hengel; Jeanne Jury; Solène Conrad; Sandra Mercier; Grace Yoon; Melissa Tsuboyama; Giulia Barcia; Cyril Gitiaux; Marlène Rio; Andrea Bevot; Sylvia Redon; Kevin Uguen; Antje Wonneberger; Alexander Schulz; Dagmar Timmann; Danielle Hays Kar...; Nicolas Chatron; Amanda Carnevale; Sonal Mahida; Katrin Õunap; Sébastien Kury; Sara Cabet; Gaetan Lesca
• Keywords: Cerebellar hypoplasia; REV-ERB; ORPHAN RECEPTOR-ALPHA; Developmental disorder; AUTISM; Myoclonic seizures; RORA; Vermian atrophy; FAMILY

Purpose: RORA encodes the RAR-related orphan receptor-alpha, playing a pivotal role in cerebellar maturation and function. Here, we report the largest series of individuals with RORA-relatedneurodevelopmental 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, lateonset, 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 n = 10/18) with a syndromic diagnosis identifiable fi able for 6: epilepsy with eyelid myoclonia (n n = 5/6) , epilepsy with myoclonic absence (n n = 1/6); specialIntscript developmental and epileptic encephalopathy (n n = 5/18); and specialIntscript unclassified fi ed (n 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 , a spectrum of myoclonic epilepsy. (c) 2024 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).