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

Over 1,500 variants in the ABCA4 locus cause phenotypes ranging from severe, early-onset retinal degeneration to very late-onset maculopathies. The resulting ABCA4/Stargardt disease is the most prevalent Mendelian eye disorder, although its underlying clinical heterogeneity, including penetrance of many alleles, are not well-understood. We hypothesized that a share of this complexity is explained by trans-modifiers, i.e., variants in unlinked loci, which are currently unknown. We sought to identify these by performing exome sequencing in a large cohort for a rare disease of 622 cases and compared variation in seven genes known to clinically phenocopy ABCA4 disease to cohorts of ethnically matched controls. We identified a significant enrichment of variants in 2 out of the 7 genes. Moderately rare, likely functional, variants, at the minor allele frequency (MAF) <0.005 and CADD>25, were enriched in ROM1, where 1.3% of 622 patients harbored a ROM1 variant compared to 0.3% of 10,865 controls (p = 2.41E04; OR 3.81 95% CI [1.77; 8.22]). More importantly, analysis of common variants (MAF>0.1) identified a frequent haplotype in PRPH2, tagged by the p.Asp338 variant with MAF = 0.21 in the matched general population that was significantly increased in the patient cohort, MAF 0.25, p = 0.0014. Significant differences were also observed between ABCA4 disease subgroups. In the late-onset subgroup, defined by the hypomorphic p.Asn1868Ile variant and including c.4253+43G>A, the allele frequency for the PRPH2 p.Asp338 variant was 0.15 vs 0.27 in the remaining cohort, p = 0.00057. Known functional data allowed suggesting a mechanism by which the PRPH2 haplotype influences the ABCA4 disease penetrance. These associations were replicated in an independent cohort of 408 patients. The association was highly statistically significant in the combined cohorts of 1030 cases, p = 4.00E-05 for all patients and p = 0.00014 for the hypomorph subgroup, suggesting a substantial trans-modifying role in ABCA4 disease for both rare and common variants in two unlinked loci. Author summary: Although recent studies have deciphered most of the genetic variation underlying ABCA4/Stargardt disease, including non-coding variants and cis-modifiers in the ABCA4 locus, many causal and modifying variants are still unknown. Here, we take advantage of recent advances in genetic and clinical methodology, and large for a Mendelian disease fully characterized patient cohorts, to examine the role of rare and common genetic variants in unlinked loci; i.e., trans-modifiers, for ABCA4-associated phenotypes. By examining 622 patients with ABCA4 disease, we show that rare variants in the ROM1 gene and a common haplotype in the PRPH2 gene are associated with ABCA4 disease overall, and with a specific disease subgroup. We replicated these findings in an independent cohort of 408 patients and suggest a mechanism for how the unlinked variation may functionally influence the penetrance of ABCA4 disease. These associations are true for populations of mostly European descent and suggest trans-modifying events in ABCA4/Stargardt disease by variation in other, unlinked, genes. They also serve as an example for other, considered "simple monogenetic", Mendelian diseases where careful consideration should be given to both rare and common variation in unlinked loci. [ABSTRACT FROM AUTHOR]