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