RORA encodes the Retinoic Acid Receptor (RAR)-related orphan receptor alpha (ROR alpha). It belongs to a family of nuclear receptors whose alterations contribute to various disorders, including central nervous system (CNS) conditions, cancer, and metabolic disorders. RORα acts as a ligand responsive heterodimer with retinoid X receptor (RXR). However, RORα isoforms 1 and 2 constitutively activate transcription and bind DNA as monomers at ROR responsive elements (RORE) which consist of 6-bp AT-rich sequences. The amino-terminal domain of the RORα1 isoform determines its affinity and specific DNA binding properties by acting in concert with the zinc finger domain. RORα is abundant particularly in the Purkinje cells of the cerebellum, where it contributes to differentiation and survival processes.
In the first report of 13 unrelated families, 13 different heterozygous single nucleotide variants or CNVs (deletions or duplications) were identified in RORA impacting a total of 16 individuals with neurodevelopmental disorders. The de novo status was confirmed for 11 of them (paternal DNA sample was unavailable in one family). Variants were either missense, nonsense, splice site substitutions, frameshift deletions or CNV deletions or duplications. A dichotomous direction of effect was observed between loss-of-function variants leading to haploinsufficiency and dominant toxic variants.