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RORB encodes the retinoic acid receptor-related orphan receptor β, a nuclear receptor highly expressed in cortex, thalamus, and retina. Loss or alteration of RORB disrupts neuronal differentiation and network excitability, predisposing to epileptic syndromes. Initial evidence arose from a de novo 9q21.13 microdeletion encompassing RORB in a patient with partial epilepsy and mild intellectual disability ([PMID:24355400]).
Autosomal dominant inheritance is supported by heterozygous variants in unrelated individuals. To date, at least 13 probands have been reported: one with a de novo microdeletion, one with a splice-site variant, and 11 individuals from four multiplex families ([PMID:24355400], [PMID:39897619], [PMID:32162308]).
The variant spectrum includes missense (n=3), nonsense (n=2), splice-site (n=1), and exon deletion (n=1) alleles. A recurrent missense, c.1162A>T (p.Ile388Phe), and two early-termination variants, c.538C>T (p.Gln180Ter) and c.196C>T (p.Arg66Ter), have been reported in photosensitive and generalized epilepsy ([PMID:32162308]).
Segregation analysis demonstrates co-segregation of RORB variants with epilepsy in four families, accounting for 11 additional affected relatives, and absence of these alleles in population databases ([PMID:32162308]).
Functional evidence is currently limited: the c.94-1G>A splice variant disrupts normal splicing, inducing premature termination of RORB protein in patient-derived cells ([PMID:39897619]). No conflicting data have been published to date.
Collectively, these studies establish a strong gene–disease association with consistent autosomal dominant inheritance, multiple unrelated families, segregation, and a mechanistic basis for RORB-mediated epilepsy. RORB variant testing is clinically useful for diagnosing idiopathic generalized, photosensitive, and occipital lobe epilepsies.
Gene–Disease AssociationStrong13 probands across five pedigrees with heterozygous RORB variants, multi-family segregation, concordant CNV data Genetic EvidenceStrongHeterozygous likely pathogenic variants identified in 13 individuals, including de novo deletion, splice-site, missense, and LoF alleles with segregation in four families Functional EvidenceLimitedSplice-site variant shown to disrupt RORB mRNA splicing in patient cells |