WFS1-Associated Optic Neuropathy: Genotype-Phenotype Correlations and Disease Progression

Area of Science:

• Ophthalmology
• Genetics
• Neuroscience

Background:

• WFS1-associated optic neuropathy (WON) is a rare condition affecting vision.
• Understanding genotype-phenotype correlations is crucial for diagnosis and management.

Purpose of the Study:

• To investigate the patterns of vision loss in WON.
• To establish genotype-phenotype correlations in patients with WFS1 variants.

Main Methods:

• A multicenter cohort study of 37 patients with WFS1 variants.
• Comprehensive ophthalmologic assessments, including visual electrophysiology and psychophysical testing.
• Complementary metabolomic analysis.

Main Results:

• Identified 22 recessive and 5 dominant WFS1 variants, including 4 novel ones.
• All variants led to loss of macular retinal ganglion cells (RGCs) and affected RGC subpopulations.
• Dominant variants showed abnormal outer plexiform layer (OPL) reflectivity on OCT and milder vision loss compared to recessive variants.

Conclusions:

• WFS1 variants cause heterogeneous phenotypes influenced by inheritance and specific alleles.
• Biallelic WFS1 variants result in more variable and severe vision loss than heterozygous variants.
• Abnormal OPL lamination on OCT is a key indicator of dominant WON.