RORA-neurodevelopmental disorder: a unique triad of developmental disability, cerebellar anomalies, and myoclonic seizures.

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.