Mariagrazia Talarico, Julitta de Bellescize, 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 Karlowicz, Nicolas Chatron, Amanda Carnevale, Sonal Mahida, Katrin Õunap, Sébastien Kury, Sara Cabet, Gaetan Lesca
{"title":"RORA-neurodevelopmental disorder: a unique triad of developmental disability, cerebellar anomalies, and myoclonic seizures.","authors":"Mariagrazia Talarico, Julitta de Bellescize, 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 Karlowicz, Nicolas Chatron, Amanda Carnevale, Sonal Mahida, Katrin Õunap, Sébastien Kury, Sara Cabet, Gaetan Lesca","doi":"10.1016/j.gim.2024.101347","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>RORA encodes the RAR-related orphan receptor-α (RORα), playing a pivotal role in cerebellar maturation and function. Here, we report the largest series of individuals with RORA-related-neurodevelopmental disorder (RORA-NDD).</p><p><strong>Methods: </strong>Forty individuals (30 unrelated; 10 siblings from 4 families) carrying RORA pathogenic/likely pathogenic variants were collected through an international collaboration.</p><p><strong>Results: </strong>The 33 variants (29 de novo, 4 inherited, one 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 (DBD). Epilepsy (n=18/38), with prominent myoclonic seizure types (n=11/18), was classified in: i) genetic generalized epilepsy (n=10/18) with a syndromic diagnosis identifiable for six: epilepsy with eyelid myoclonia (n=5/6), epilepsy with myoclonic absence (n=1/6); ii) developmental and epileptic encephalopathy (n=5/18); and iii) unclassified (n=3/18). A participant with rapid deterioration of visual acuity and cone/rod dystrophy was reported.</p><p><strong>Conclusion: </strong>Missense variants in DBD correlate to a more severe cerebellar phenotype. The RORA-NDD triad comprises developmental disability, cerebellar features and a spectrum of myoclonic epilepsy.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101347"},"PeriodicalIF":6.6000,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Genetics in Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.gim.2024.101347","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
引用次数: 0
Abstract
Purpose: RORA encodes the RAR-related orphan receptor-α (RORα), playing a pivotal role in cerebellar maturation and function. Here, we report the largest series of individuals with RORA-related-neurodevelopmental disorder (RORA-NDD).
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, one 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 (DBD). Epilepsy (n=18/38), with prominent myoclonic seizure types (n=11/18), was classified in: i) genetic generalized epilepsy (n=10/18) with a syndromic diagnosis identifiable for six: epilepsy with eyelid myoclonia (n=5/6), epilepsy with myoclonic absence (n=1/6); ii) developmental and epileptic encephalopathy (n=5/18); and iii) unclassified (n=3/18). A participant with rapid deterioration of visual acuity and cone/rod dystrophy was reported.
Conclusion: Missense variants in DBD correlate to a more severe cerebellar phenotype. The RORA-NDD triad comprises developmental disability, cerebellar features and a spectrum of myoclonic epilepsy.
期刊介绍:
Genetics in Medicine (GIM) is the official journal of the American College of Medical Genetics and Genomics. The journal''s mission is to enhance the knowledge, understanding, and practice of medical genetics and genomics through publications in clinical and laboratory genetics and genomics, including ethical, legal, and social issues as well as public health.
GIM encourages research that combats racism, includes diverse populations and is written by authors from diverse and underrepresented backgrounds.