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 , Gaetan Lesca
{"title":"rora -神经发育障碍:一种独特的发育障碍、小脑异常和肌阵挛性癫痫。","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 , Gaetan Lesca","doi":"10.1016/j.gim.2024.101347","DOIUrl":null,"url":null,"abstract":"<div><h3>Purpose</h3><div><em>RORA</em> 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 <em>RORA</em>-related-neurodevelopmental disorder.</div></div><div><h3>Methods</h3><div>Forty individuals (30 unrelated; 10 siblings from 4 families) carrying <em>RORA</em> pathogenic/likely pathogenic variants were collected through an international collaboration.</div></div><div><h3>Results</h3><div>The 33 variants (29 de novo, 4 inherited, and 1 shared), identified by genome/exome sequencing (<em>n</em> = 21), chromosomal microarray analysis (<em>n</em> = 7), or gene panels (<em>n</em> = 4), included frameshift (<em>n</em> = 18/33), missense (<em>n</em> = 9/33), and stop codon (<em>n</em> = 6/33). Developmental disability (<em>n</em> = 32/37), intellectual disability (<em>n</em> = 22/32), and cerebellar signs (<em>n</em> = 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 (<em>n</em> = 16/25) were more frequent in individuals with missense variants in the DNA-binding domain. Epilepsy (<em>n</em> = 18/38), with prominent myoclonic seizure types (<em>n</em> = 11/18), was classified in (1) genetic generalized epilepsy (<em>n</em> = 10/18) with a syndromic diagnosis identifiable for 6: epilepsy with eyelid myoclonia (<em>n</em> = 5/6) and epilepsy with myoclonic absence (<em>n</em> = 1/6); (2) developmental and epileptic encephalopathy (<em>n</em> = 5/18); and (3) unclassified (<em>n</em> = 3/18). A participant with rapid deterioration of visual acuity and cone/rod dystrophy was reported.</div></div><div><h3>Conclusion</h3><div>Missense variants in DNA-binding domain correlate to a more severe cerebellar phenotype. The <em>RORA</em>-related-neurodevelopmental disorder triad comprises developmental disability, cerebellar features, and a spectrum of myoclonic epilepsy.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 4","pages":"Article 101347"},"PeriodicalIF":6.6000,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"RORA-neurodevelopmental disorder: A unique triad of developmental disabilities, 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 , Gaetan Lesca\",\"doi\":\"10.1016/j.gim.2024.101347\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Purpose</h3><div><em>RORA</em> 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 <em>RORA</em>-related-neurodevelopmental disorder.</div></div><div><h3>Methods</h3><div>Forty individuals (30 unrelated; 10 siblings from 4 families) carrying <em>RORA</em> pathogenic/likely pathogenic variants were collected through an international collaboration.</div></div><div><h3>Results</h3><div>The 33 variants (29 de novo, 4 inherited, and 1 shared), identified by genome/exome sequencing (<em>n</em> = 21), chromosomal microarray analysis (<em>n</em> = 7), or gene panels (<em>n</em> = 4), included frameshift (<em>n</em> = 18/33), missense (<em>n</em> = 9/33), and stop codon (<em>n</em> = 6/33). Developmental disability (<em>n</em> = 32/37), intellectual disability (<em>n</em> = 22/32), and cerebellar signs (<em>n</em> = 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 (<em>n</em> = 16/25) were more frequent in individuals with missense variants in the DNA-binding domain. Epilepsy (<em>n</em> = 18/38), with prominent myoclonic seizure types (<em>n</em> = 11/18), was classified in (1) genetic generalized epilepsy (<em>n</em> = 10/18) with a syndromic diagnosis identifiable for 6: epilepsy with eyelid myoclonia (<em>n</em> = 5/6) and epilepsy with myoclonic absence (<em>n</em> = 1/6); (2) developmental and epileptic encephalopathy (<em>n</em> = 5/18); and (3) unclassified (<em>n</em> = 3/18). A participant with rapid deterioration of visual acuity and cone/rod dystrophy was reported.</div></div><div><h3>Conclusion</h3><div>Missense variants in DNA-binding domain correlate to a more severe cerebellar phenotype. The <em>RORA</em>-related-neurodevelopmental disorder triad comprises developmental disability, cerebellar features, and a spectrum of myoclonic epilepsy.</div></div>\",\"PeriodicalId\":12717,\"journal\":{\"name\":\"Genetics in Medicine\",\"volume\":\"27 4\",\"pages\":\"Article 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://www.sciencedirect.com/science/article/pii/S1098360024002818\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"GENETICS & HEREDITY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Genetics in Medicine","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1098360024002818","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
RORA-neurodevelopmental disorder: A unique triad of developmental disabilities, cerebellar anomalies, and myoclonic seizures
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.
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.