Novel RORA Variants Reveal Genotype-Phenotype Diversity and Variable Expressivity in Neurodevelopmental Disorders

Area of Science:

• Genetics
• Neurodevelopmental Biology
• Molecular Biology

Background:

• The RAR-related orphan receptor alpha (RORA) gene is crucial for transcriptional regulation, circadian rhythm, and neurodevelopment.
• Dominant RORA variants are linked to intellectual developmental disorder, epilepsy, and cerebellar ataxia, but the full spectrum of symptoms is unclear.

Purpose of the Study:

• To investigate the genotypic and phenotypic spectrum of RORA-related neurodevelopmental disorders.
• To analyze comprehensive genetic and clinical data from individuals with RORA variants.

Main Methods:

• Whole exome sequencing and chromosomal microarray analysis were used to identify RORA variants.
• Sanger sequencing confirmed identified variants.
• Clinical data from affected individuals were collected and analyzed.

Main Results:

• Three distinct RORA variants were identified: a deletion encompassing RORA, a de novo nonsense variant, and a novel heterozygous frameshift variant.
• Clinical presentations ranged from severe neurodevelopmental delay and epilepsy to mild intellectual disability and behavioral issues.
• The study observed significant intrafamilial variability and variable expressivity, with the same variant causing different phenotypes within a family.

Conclusions:

• The findings expand the known genotypic and phenotypic spectrum of RORA-related neurodevelopmental disorders.
• Intrafamilial variability and variable expressivity are key features of RORA-associated pathogenesis.
• Future genotype-phenotype studies should consider the impact of variable expressivity in RORA disorders.