{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T12:48:34Z","timestamp":1782478114295,"version":"3.54.5"},"reference-count":44,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:00:00Z","timestamp":1782432000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:00:00Z","timestamp":1782432000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Acta Ophthalmologica"],"abstract":"Abstract<\/jats:title>\n \n Purpose<\/jats:title>\n Retinitis pigmentosa (RP) is an inherited retinal disease (IRD), whereby each affected individual typically harbours pathogenic variants in a single causative gene, yet the disorder exhibits marked genetic heterogeneity, with more than 100 genes reported to underlie RP. Dual\u2010gene defect constellations are rare but may modify disease presentation, complicating diagnosis, prognosis and therapeutic decision\u2010making. This study aimed to characterize the clinical and genetic effects of dual\u2010gene variants in patients with RP as the lead diagnosis.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We retrospectively analysed 10 affected individuals and their parents from eight families with confirmed dual\u2010genotype constellations in RP\u2010associated genes. Ophthalmic evaluation included best\u2010corrected visual acuity (BCVA), visual fields, multimodal imaging, electroretinography (ERG) and full\u2010field stimulus threshold testing (FST). Genetic analyses comprised whole genome sequencing and targeted segregation studies; for the latter, long\u2010read sequencing was used to clarify\n cis\/trans<\/jats:italic>\n variant configuration.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Genes involved were\n CEP290<\/jats:italic>\n ,\n RCBTB1<\/jats:italic>\n ,\n ABCA4<\/jats:italic>\n ,\n PDE6A<\/jats:italic>\n ,\n CRB1<\/jats:italic>\n ,\n EYS<\/jats:italic>\n ,\n PRPH2<\/jats:italic>\n ,\n MYO7A<\/jats:italic>\n ,\n RS1<\/jats:italic>\n ,\n USH2A<\/jats:italic>\n ,\n MT\u2010TL1<\/jats:italic>\n ,\n RHO<\/jats:italic>\n and\n BEST1<\/jats:italic>\n , in various genotype constellations. Phenotypes ranged from early\u2010onset severe rod\u2010cone dystrophy to late\u2010onset mild RP, largely reflecting gene\u2010specific effects (e.g.\n EYS<\/jats:italic>\n \u2009>\u2009\n CRB1<\/jats:italic>\n \u2009>\u2009\n PRPH2<\/jats:italic>\n ) and their interactions. Long\u2010read sequencing revealed\n ABCA4<\/jats:italic>\n variants\n in cis<\/jats:italic>\n , explaining asymptomatic carriers and informing gene therapy eligibility. Functional retinal testing highlighted gene\u2010specific patterns, including macular preservation in\n EYS<\/jats:italic>\n \u2010driven RP and Best disease\u2010associated macular changes.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n Dual\u2010gene variant constellations contribute to heterogeneous RP phenotypes. Integrating comprehensive genetic analysis with detailed clinical assessment is critical to define gene\u2010specific contributions, inform prognosis, guide clinical management and determine eligibility for emerging gene\u2010based therapies.<\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/aos.70181","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T12:08:48Z","timestamp":1782475728000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical manifestations of dual\u2010gene variants in retinitis pigmentosa"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1549-5889","authenticated-orcid":false,"given":"Lasse","family":"Wolfram","sequence":"first","affiliation":[{"name":"Department for Ophthalmology, University Eye Clinic Eberhard Karls University of T\u00fcbingen T\u00fcbingen Germany"},{"name":"Department for Ophthalmology, Institute for Ophthalmic Research Eberhard Karls University of T\u00fcbingen T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0673-9987","authenticated-orcid":false,"given":"Jan\u2010Philipp","family":"Bodenbender","sequence":"additional","affiliation":[{"name":"Department for Ophthalmology, University Eye Clinic Eberhard Karls University of T\u00fcbingen T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4485-5580","authenticated-orcid":false,"given":"David A.","family":"Merle","sequence":"additional","affiliation":[{"name":"Department for Ophthalmology, University Eye Clinic Eberhard Karls University of T\u00fcbingen T\u00fcbingen Germany"},{"name":"Department for Ophthalmology, Institute for Ophthalmic Research Eberhard Karls University of T\u00fcbingen T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milda","family":"Reith","sequence":"additional","affiliation":[{"name":"Department for Ophthalmology, University Eye Clinic Eberhard Karls University of T\u00fcbingen T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3624-8318","authenticated-orcid":false,"given":"Anton","family":"Sonntag","sequence":"additional","affiliation":[{"name":"Department for Ophthalmology, University Eye Clinic Eberhard Karls University of T\u00fcbingen T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krunoslav","family":"Stingl","sequence":"additional","affiliation":[{"name":"Department for Ophthalmology, University Eye Clinic Eberhard Karls University of T\u00fcbingen T\u00fcbingen Germany"},{"name":"Center for Rare Eye Diseases Eberhard Karls University of T\u00fcbingen T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias B.","family":"Haack","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and Applied Genomics Eberhard Karls University of T\u00fcbingen T\u00fcbingen Germany"},{"name":"Center for Rare Disease Eberhard Karls University of T\u00fcbingen T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresia","family":"Zuleger","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and Applied Genomics Eberhard Karls University of T\u00fcbingen T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernd","family":"Wissinger","sequence":"additional","affiliation":[{"name":"Department for Ophthalmology, Institute for Ophthalmic Research Eberhard Karls University of T\u00fcbingen T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"K\u00fchlewein","sequence":"additional","affiliation":[{"name":"Department for Ophthalmology, University Eye Clinic Eberhard Karls University of T\u00fcbingen T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarina","family":"Stingl","sequence":"additional","affiliation":[{"name":"Department for Ophthalmology, University Eye Clinic Eberhard Karls University of T\u00fcbingen T\u00fcbingen Germany"},{"name":"Center for Rare Eye Diseases Eberhard Karls University of T\u00fcbingen T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Kohl","sequence":"additional","affiliation":[{"name":"Department for Ophthalmology, Institute for Ophthalmic Research Eberhard Karls University of T\u00fcbingen T\u00fcbingen Germany"},{"name":"Center for Rare Eye Diseases Eberhard Karls University of T\u00fcbingen T\u00fcbingen 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