{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T02:13:24Z","timestamp":1790475204883,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.pgen.1010129","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,4,11]],"date-time":"2022-04-11T00:00:00Z","timestamp":1649635200000}}],"reference-count":52,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2022,3,30]],"date-time":"2022-03-30T00:00:00Z","timestamp":1648598400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["R01EY028203; R01EY028954; R01EY029315; P30EY019007"],"award-info":[{"award-number":["R01EY028203; R01EY028954; R01EY029315; P30EY019007"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001116","name":"Foundation Fighting Blindness","doi-asserted-by":"publisher","award":["PPA-1218-0751-COLU"],"award-info":[{"award-number":["PPA-1218-0751-COLU"]}],"id":[{"id":"10.13039\/100001116","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001818","name":"Research to Prevent Blindness","doi-asserted-by":"publisher","award":["Unrestricted Funds"],"award-info":[{"award-number":["Unrestricted Funds"]}],"id":[{"id":"10.13039\/100001818","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Pangere Family Foundation"},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["Intramural Research Program of the NIH"],"award-info":[{"award-number":["Intramural Research Program of the NIH"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["EY022356; EY018571; EY002520, S10OD023469"],"award-info":[{"award-number":["EY022356; EY018571; EY002520, S10OD023469"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>Over 1,500 variants in the <jats:italic>ABCA4<\/jats:italic> 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 <jats:italic>trans<\/jats:italic>-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) &lt;0.005 and CADD&gt;25, were enriched in <jats:italic>ROM1<\/jats:italic>, where 1.3% of 622 patients harbored a <jats:italic>ROM1<\/jats:italic> 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&gt;0.1) identified a frequent haplotype in <jats:italic>PRPH2<\/jats:italic>, 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&gt;A, the allele frequency for the <jats:italic>PRPH2<\/jats:italic> 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 <jats:italic>PRPH2<\/jats:italic> 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 1,030 cases, p = 4.00E-05 for all patients and p = 0.00014 for the hypomorph subgroup, suggesting a substantial <jats:italic>trans<\/jats:italic>-modifying role in ABCA4 disease for both rare and common variants in two unlinked loci.<\/jats:p>","DOI":"10.1371\/journal.pgen.1010129","type":"journal-article","created":{"date-parts":[[2022,3,30]],"date-time":"2022-03-30T17:37:29Z","timestamp":1648661849000},"page":"e1010129","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":18,"title":["Rare and common variants in ROM1 and PRPH2 genes trans-modify Stargardt\/ABCA4 disease"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3749-4799","authenticated-orcid":true,"given":"Jana","family":"Zernant","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Winston","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9821-7704","authenticated-orcid":true,"given":"Kerry","family":"Goetz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0107-6608","authenticated-orcid":true,"given":"Ehsan","family":"Ullah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayuki","family":"Nagasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei-Yin","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerald 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Burkard","year":"2018","journal-title":"J Clin Invest"},{"key":"pgen.1010129.ref008","doi-asserted-by":"crossref","first-page":"100861","DOI":"10.1016\/j.preteyeres.2020.100861","article-title":"Clinical spectrum, genetic complexity and therapeutic approaches for retinal disease caused by ABCA4 mutations.","volume":"79","author":"FPM Cremers","year":"2020","journal-title":"Prog Retin Eye Res"},{"issue":"1","key":"pgen.1010129.ref009","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.ophtha.2017.07.019","article-title":"The Rapid-Onset Chorioretinopathy Phenotype of ABCA4 Disease.","volume":"125","author":"K Tanaka","year":"2018","journal-title":"Ophthalmology"},{"issue":"4","key":"pgen.1010129.ref010","doi-asserted-by":"crossref","DOI":"10.1101\/mcs.a002733","article-title":"Extremely hypomorphic and severe deep intronic variants in the ABCA4 locus result in varying Stargardt disease phenotypes.","volume":"4","author":"J Zernant","year":"2018","journal-title":"Cold 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