The Challenge of VUS in Inherited Retinal Degeneration: Insight from Functional Studies.

Area of Science:

• Genetics
• Ophthalmology
• Molecular Biology

Background:

• DNA sequencing advances increase genetic variant identification, posing interpretation challenges.
• Variants of Uncertain Significance (VUS) complicate diagnosis and patient care for inherited retinal degenerations (IRDs).
• Over 40% of variants in IRD-associated genes are currently classified as VUS.

Purpose of the Study:

• To review the application of functional analyses in interpreting VUS in IRD genes.
• To discuss the utility of various functional assays in determining variant pathogenicity.
• To highlight the impact of functional data on understanding IRD mechanisms and patient management.

Main Methods:

• Review of literature on functional analysis techniques for IRD variants.
• Categorization of different types of functional assays used.
• Evaluation of the utility of these assays in pathogenicity assessment.

Main Results:

• Functional analyses are essential tools for resolving VUS in IRD genetics.
• Diverse assays exist, each offering unique insights into variant function and disease association.
• Clarifying pathogenicity through functional studies directly impacts clinical diagnosis and therapeutic strategies.

Conclusions:

• Functional analyses are critical for accurate interpretation of genetic variants in IRDs.
• These methods enhance understanding of disease mechanisms and improve patient diagnostic and care pathways.
• The strategic application of functional assays is key to overcoming the VUS challenge in IRD genetic testing.