Novel RORA variants reveal genotype-phenotype diversity and variable expressivity in neurodevelopmental disorders

Abstract

The RAR-related orphan receptor alpha (RORA) gene encodes a nuclear receptor involved in transcriptional regulation, circadian rhythm, and neurodevelopment. Dominant RORA variants are associated with intellectual developmental disorder with or without epilepsy or cerebellar ataxia, yet the phenotypic spectrum remains poorly defined. We performed comprehensive genetic and clinical analyses in four individuals with RORA variants from three unrelated families, using whole exome sequencing and chromosomal microarray analysis. Identified variants were confirmed by Sanger sequencing. Genetic analyses revealed three distinct RORA variants: a 15q21.2-q22.2 deletion encompassing RORA, a de novo nonsense variant c.499C>T (p.Gln167*), and a novel heterozygous frameshift variant c.683_686del (p.Glu228Valfs*78) segregating within a family. Clinical findings ranged from severe neurodevelopmental delay and epilepsy to mild intellectual disability and behavioral abnormalities, demonstrating marked intrafamilial variability. Notably, the same frameshift variant presented with differing phenotypes in the family, indicating variable expressivity-the first such observation reported in RORA-related disorders. Our findings broaden the genotypic and phenotypic spectrum of RORA-related neurodevelopmental disorders. The observed intrafamilial variability highlights the complexity of RORA-associated pathogenesis and underscores the importance of considering variable expressivity in future genotype-phenotype studies.