Genetic screening for macular dystrophies in patients clinically diagnosed with dry age-related macular degeneration

Area of Science:

• Ophthalmology
• Genetics
• Retinal Diseases

Background:

• Clinical differentiation between dry age-related macular degeneration (AMD) and AMD-mimicking dystrophies presents diagnostic challenges.
• Accurate diagnosis is critical for patient selection in clinical trials for emerging dry AMD therapies.

Purpose of the Study:

• To evaluate the prevalence of AMD-mimicking dystrophies within a cohort of patients diagnosed with AMD.
• To assess the utility of whole-exome sequencing (WES) in identifying genetic causes of macular dystrophies that mimic AMD.

Main Methods:

• Whole-exome sequencing (WES) was conducted on 218 patients with intermediate AMD or geographic atrophy and 133 controls.
• WES data was analyzed for rare variants in 19 genes linked to autosomal dominant and recessive macular dystrophies.

Main Results:

• Pathogenic variants in PRPH2 (c.424C>T; p.R142W) causing autosomal dominant central areolar choroidal dystrophy (CACD) were found in 3 (1.4%) of AMD patients, all presenting with geographic atrophy.
• Heterozygous variants of unknown but potentially high clinical significance were identified in 12 (5.5%) patients within genes associated with autosomal dominant macular dystrophies.

Conclusions:

• Distinguishing AMD from mimicking dystrophies like CACD solely on fundus examination can be difficult.
• Genetic screening, especially targeting genes like PRPH2, is valuable for identifying AMD-mimicking dystrophies and ensuring accurate diagnosis.