Clinical and functional heterogeneity associated with the disruption of retinoic acid receptor beta

Area of Science:

• Genetics
• Developmental Biology
• Ophthalmology

Background:

• Dominant variants in the retinoic acid receptor beta (RARB) gene are linked to MCOPS12, a syndrome characterized by microphthalmia, birth anomalies, and developmental delay.
• MCOPS12 presents with global developmental delay, spasticity, and/or dystonia, alongside other potential birth defects.

Purpose of the Study:

• To functionally characterize novel pathogenic and likely pathogenic variants in RARB.
• To describe the clinical spectrum of MCOPS12 associated with RARB disruption.

Main Methods:

• In vitro transcriptional assays were employed to assess variant function.
• In silico structural analysis was used to evaluate the impact of variants on retinoid response.
• Clinical data from 52 affected individuals were reviewed to delineate the phenotype.

Main Results:

• Seventeen novel pathogenic or likely pathogenic variants in RARB were identified in 25 affected individuals.
• All tested RARB variants demonstrated either gain-of-function or loss-of-function activity.
• Loss-of-function variants exerted a dominant-negative effect, potentially impairing ligand binding or coactivator recruitment.
• Clinical review revealed a broader MCOPS12 phenotype than previously recognized, with variability in cardinal features like eye anomalies and motor impairment.

Conclusions:

• Pathogenic variants in RARB exhibit functional heterogeneity.
• RARB variants are associated with extensive clinical heterogeneity in MCOPS12.
• The study expands the understanding of RARB-related disorders and their variable clinical manifestations.