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

Abstract

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.

Towards Uncovering the Role of Incomplete Penetrance in Maculopathies through Sequencing of 105 Disease-Associated Genes

“…In fact, the presence of p.(Leu114Alafs*18) with p.(Arg142Trp) in a patient with autosomal dominant CACD has previously been described [ 54 ]. Moreover, rare variants in ROM1 and a common PRPH2 haplotype are proposed to be the modifiers of ABCA4 -associated disease [ 56 ]. Despite previous examples of digenic inheritance of ROM1 and PRPH2 , no PRPH2 or ABCA4 variants were identified in proband 079830, although high sequencing coverage was observed over the targeted regions.…”

Compendium of clinical variant classification for 2,247 uniqueABCA4variants to improve genetic medicine access for Stargardt Disease

“…Modifiers seem to play a role in ABCA4-retinopathies and may explain this reduced penetrance of variants. A sex imbalance has been reported for individuals having mild likely reduced penetrant variants [15] and common PRPH2 variants and rare ROM1 variants have been reported to act as modifiers of ABCA4-retinopathies [34]. In three Dutch families with biallelic sibling pairs carrying c.5603A>T in trans with another severe ABCA4 variant, not all siblings were affected by ABCA4retinopathy [14].…”

Compendium of Clinical Variant Classification for 2,246 Unique ABCA4 Variants to Clarify Variant Pathogenicity in Stargardt Disease Using a Modified ACMG/AMP Framework

“…Modifiers seem to play a role in ABCA4-AR and may explain the occurrence of variants with reduced penetrance. A sex imbalance has been reported for individuals having mild likely reduced penetrant variants [15], and common PRPH2 variants and rare ROM1 variants have been reported to act as modifiers of ABCA4-AR [46]. In three Dutch families with biallelic sibling pairs carrying c.5603A>T in trans with another severe ABCA4 variant, not all siblings were affected by ABCA4-AR [14].…”