Rare and common variants in ROM1 and PRPH2 genes trans-modify Stargardt/ABCA4 disease

Area of Science:

• Genetics
• Ophthalmology
• Molecular Biology

Background:

• ABCA4/Stargardt disease is the most common Mendelian eye disorder, caused by over 1,500 variants in the ABCA4 gene.
• Significant clinical heterogeneity and incomplete penetrance complicate the understanding of ABCA4 disease.
• The role of unlinked genetic modifiers (trans-modifiers) in ABCA4 disease complexity is largely unknown.

Purpose of the Study:

• To identify trans-modifiers that contribute to the clinical heterogeneity of ABCA4/Stargardt disease.
• To investigate the potential role of variants in seven known phenocopy genes as modifiers.

Main Methods:

• Exome sequencing was performed on a cohort of 622 patients with ABCA4 disease.
• Variant analysis compared patient data to ethnically matched control cohorts (10,865 individuals).
• Statistical analyses identified significant enrichment of variants in ROM1 and PRPH2 genes.
• Replication analysis was conducted in an independent cohort of 408 patients.

Main Results:

• Rare variants in ROM1 were significantly enriched in patients (1.3% vs 0.3% in controls, p = 2.41E-04).
• A common PRPH2 haplotype, tagged by p.Asp338 (MAF=0.21), was significantly increased in patients (MAF=0.25, p = 0.0014).
• The PRPH2 p.Asp338 variant showed differential frequencies in late-onset ABCA4 disease subgroups.
• Associations were replicated in an independent cohort, confirming a substantial trans-modifying role.

Conclusions:

• Both rare (ROM1) and common (PRPH2) variants in unlinked loci act as significant trans-modifiers in ABCA4/Stargardt disease.
• These genetic modifiers contribute to the clinical heterogeneity and penetrance of ABCA4 disease.
• The identified PRPH2 haplotype may influence ABCA4 disease progression through a proposed functional mechanism.