{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T15:11:12Z","timestamp":1789053072398,"version":"build-2803163510"},"reference-count":31,"publisher":"American Medical Association (AMA)","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Ophthalmol"],"abstract":"\n Importance<\/jats:title>\n \n Doyne honeycomb retinal dystrophy or malattia leventinese (DHRD\/ML) is an autosomal dominant retinal disorder caused by a single recurrent p.Arg345Trp (NM_001039348.3:c.1033C&amp;gt;T) variant in\n EFEMP1<\/jats:italic>\n and characterized by early-onset, nearly confluent, large central retinal drusen. Other variants in\n EFEMP1<\/jats:italic>\n have not been reported to cause retinal disease.\n <\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n \n To define the topography of the anatomical and functional phenotype of another variant in\n EFEMP1<\/jats:italic>\n , p.Arg140Trp (c.418C&amp;gt;T), associated with retinal degeneration.\n <\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n This multi-institutional case series was conducted at 3 inherited retinal disease clinics (Philadelphia, Pennsylvania; Basel, Switzerland; and Prague, Czech Republic) from October 1998 to May 2026. Participants included 3 unrelated families with the p.Arg140Trp variant and 1 comparator family with canonical DHRD\/ML caused by the p.Arg345Trp variant. Analyses were conducted from November 2019 to May 2026.<\/jats:p>\n <\/jats:sec>\n \n Exposure<\/jats:title>\n \n Heterozygosity for pathogenic\n EFEMP1<\/jats:italic>\n variants.\n <\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n Color fundus photography and optical coherence tomography, light- and dark-adapted chromatic perimetry, and rod-mediated dark adaptation kinetics.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n The\n EFEMP1<\/jats:italic>\n p.Arg140Trp variant segregated with disease in all 3 families. In family 1, the index case developed nyctalopia in the sixth decade with progressive field loss and abnormal ERG. Among 5 at-risk relatives (ages 50 to 58 years), 4 heterozygous carriers had delayed rod-mediated dark adaptation kinetics despite best-corrected visual acuity of 20\/20 OU and normal fundus appearance; the noncarrier had normal imaging and function. Additional heterozygous carriers from families 2 (age 42 years; symptom onset at 40 years) and 3 (age 69 years; symptom onset at 55 years) had nyctalopia and peripheral lobular chorioretinal atrophy initially labeled gyrate atrophy-like or choroideremia-like. Topographically matched testing in temporal retina without visible atrophy showed severe rod dysfunction and markedly delayed dark adaptation at 15\u00b0, 30\u00b0, and 46\u00b0 with increasing severity toward the periphery. For comparison, the patient with DHRD\/ML exhibited normal light- and dark-adapted visual function outside the central 10\u00b0 and an increasing delay in rod recovery kinetics toward the fovea.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n \n This study found that the\n EFEMP1<\/jats:italic>\n p.Arg140Trp variant was associated with a late-onset, predominantly peripheral retinal degeneration with features overlapping the late-onset retinal degeneration phenotype and was distinct from canonical DHRD\/ML; it spares relatively central macular structure and function while preferentially affecting the periphery. Functional evidence suggests preferential rod involvement, with rod dysfunction observed at retinal loci without detectable outer nuclear layer loss.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamaophthalmol.2026.3828","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T15:00:35Z","timestamp":1789052435000},"source":"Crossref","is-referenced-by-count":0,"title":["Widening the Spectrum of Disease Expression due to Heterozygous Variants in\n EFEMP1<\/i>"],"prefix":"10.1001","author":[{"given":"Chloe M.","family":"Stanton","sequence":"first","affiliation":[{"name":"Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, United Kingdom"},{"name":"Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg","family":"Ansari","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Basel, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Pfau","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Basel, Basel, Switzerland"},{"name":"Department of Ophthalmology, University of Bonn, Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa","family":"Lipsky","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Basel, Basel, Switzerland"},{"name":"Department of Ophthalmology, University of Bonn, Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihail","family":"Halachev","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukas","family":"Gerasimavicius","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla","family":"Drake","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph A.","family":"Marsh","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Hayward","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Sumaroka","sequence":"additional","affiliation":[{"name":"Center for Hereditary Retinal Degenerations, Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bohdan","family":"Kousal","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Li\u0161kov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic"},{"name":"Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathieu","family":"Quinodoz","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Basel, Basel, Switzerland"},{"name":"Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Rivolta","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Basel, Basel, Switzerland"},{"name":"Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomas S.","family":"Aleman","sequence":"additional","affiliation":[{"name":"Center for Hereditary Retinal Degenerations, Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Artur V.","family":"Cideciyan","sequence":"additional","affiliation":[{"name":"Center for Hereditary Retinal Degenerations, Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilian","family":"Pfau","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Basel, Basel, Switzerland"},{"name":"Department of Ophthalmology, University of Bonn, Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"issue":"9","key":"eoi260053r1","first-page":"1772","article-title":"Sub-retinal pigment epithelial deposits in a dominant late-onset retinal degeneration.","volume":"37","author":"Kuntz","year":"1996","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"15","key":"eoi260053r2","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1167\/iovs.64.15.33","article-title":"Treatment strategy with gene editing for late-onset retinal degeneration caused by a founder variant in C1QTNF5.","volume":"64","author":"Li","year":"2023","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"20","key":"eoi260053r3","doi-asserted-by":"publisher","first-page":"2657","DOI":"10.1093\/hmg\/ddg289","article-title":"Mutation in a short-chain collagen gene, CTRP5, results in extracellular deposit formation in late-onset retinal degeneration: a genetic model for age-related macular degeneration.","volume":"12","author":"Hayward","year":"2003","journal-title":"Hum Mol Genet"},{"issue":"1","key":"eoi260053r4","doi-asserted-by":"publisher","first-page":"12147","DOI":"10.1038\/s41598-017-11898-3","article-title":"Novel pathogenic mutations in C1QTNF5 support a dominant negative disease mechanism in late-onset retinal degeneration.","volume":"7","author":"Stanton","year":"2017","journal-title":"Sci Rep"},{"issue":"12","key":"eoi260053r5","doi-asserted-by":"publisher","first-page":"2256","DOI":"10.1016\/S0161-6420(00)00419-X","article-title":"Dominant late-onset retinal degeneration with regional variation of sub-retinal pigment epithelium deposits, retinal function, and photoreceptor degeneration.","volume":"107","author":"Milam","year":"2000","journal-title":"Ophthalmology"},{"issue":"20","key":"eoi260053r6","doi-asserted-by":"publisher","first-page":"2191","DOI":"10.1001\/jama.2013.281053","article-title":"World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.","volume":"310","author":"World Medical Association","year":"2013","journal-title":"JAMA"},{"issue":"1","key":"eoi260053r7","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.ajo.2010.08.047","article-title":"Appropriate use and reporting of uncontrolled case series in the medical literature.","volume":"151","author":"Kempen","year":"2011","journal-title":"Am J Ophthalmol"},{"issue":"2","key":"eoi260053r8","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1167\/iovs.66.2.17","article-title":"Topography of slowed dark adaptation in pseudoxanthoma elasticum: PROPXE study report 1.","volume":"66","author":"Pfau","year":"2025","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"13","key":"eoi260053r9","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1167\/iovs.66.13.31","article-title":"Measuring rod- and cone-photoreceptor-specific vision in inherited retinal diseases using a commercial perimeter.","volume":"66","author":"Wu","year":"2025","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"1","key":"eoi260053r10","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1186\/s13059-016-0974-4","article-title":"The ensembl variant effect predictor.","volume":"17","author":"McLaren","year":"2016","journal-title":"Genome Biol"},{"issue":"3","key":"eoi260053r11","doi-asserted-by":"publisher","DOI":"10.1093\/pnasnexus\/pgad043","article-title":"The first genetic landscape of inherited retinal dystrophies in Portuguese patients identifies recurrent homozygous mutations as a frequent cause of pathogenesis.","volume":"2","author":"Peter","year":"2023","journal-title":"Proc Natl Acad Sci U S A Nexus"},{"issue":"4","key":"eoi260053r12","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1111\/cge.14391","article-title":"MIR204 n.37C>T variant as a cause of chorioretinal dystrophy variably associated with iris coloboma, early-onset cataracts and congenital glaucoma.","volume":"104","author":"Jedlickova","year":"2023","journal-title":"Clin Genet"},{"issue":"3","key":"eoi260053r13","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1016\/j.exer.2009.09.018","article-title":"Focus on molecules: fibulin-3 (EFEMP1).","volume":"90","author":"Zhang","year":"2010","journal-title":"Exp Eye Res"},{"issue":"24","key":"eoi260053r14","doi-asserted-by":"publisher","first-page":"4765","DOI":"10.1091\/mbc.e11-08-0695","article-title":"Compromised mutant EFEMP1 secretion associated with macular dystrophy remedied by proteostasis network alteration.","volume":"22","author":"Hulleman","year":"2011","journal-title":"Mol Biol Cell"},{"issue":"21","key":"eoi260053r15","doi-asserted-by":"publisher","first-page":"5389","DOI":"10.1021\/acs.jpcb.7b11367","article-title":"Flex ddG: Rosetta ensemble-based estimation of changes in protein-protein binding affinity upon mutation.","volume":"122","author":"Barlow","year":"2018","journal-title":"J Phys Chem B"},{"issue":"6","key":"eoi260053r16","doi-asserted-by":"publisher","first-page":"1192","DOI":"10.1097\/IAE.0000000000004407","article-title":"Drusen volume as clinical outcome measure in subjects with malattia leventinese.","volume":"45","author":"Ehrenzeller","year":"2025","journal-title":"Retina"},{"issue":"8","key":"eoi260053r17","doi-asserted-by":"publisher","DOI":"10.1016\/j.xops.2026.101287","article-title":"Interactions between epidermal growth factor\u2013containing fibulin-like extracellular matrix protein 1 and tissue inhibitor of metalloproteinases-3 and relevance to age-related macular degeneration.","volume":"6","author":"Ehrenzeller","year":"2026","journal-title":"Ophthalmol Sci"},{"issue":"6","key":"eoi260053r18","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1167\/iovs.65.6.31","article-title":"A long-term retrospective natural history study of EFEMP1-associated autosomal dominant drusen.","volume":"65","author":"de Guimar\u00e3es","year":"2024","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"11","key":"eoi260053r19","doi-asserted-by":"publisher","first-page":"3973","DOI":"10.1167\/iovs.05-0070","article-title":"Aberrant accumulation of fibulin-3 in the endoplasmic reticulum leads to activation of the unfolded protein response and VEGF expression.","volume":"46","author":"Roybal","year":"2005","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"19","key":"eoi260053r20","doi-asserted-by":"publisher","first-page":"5555","DOI":"10.1093\/hmg\/ddv287","article-title":"A local complement response by RPE causes early-stage macular degeneration.","volume":"24","author":"Fernandez-Godino","year":"2015","journal-title":"Hum Mol Genet"},{"issue":"2","key":"eoi260053r21","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2026.102955","article-title":"Antisense oligonucleotide allele-specific targeting of EFEMP1 in a patient-derived model of Doyne honeycomb retinal dystrophy.","volume":"37","author":"Rezek","year":"2026","journal-title":"Mol Ther Nucleic Acids"},{"issue":"1","key":"eoi260053r22","doi-asserted-by":"publisher","first-page":"2998","DOI":"10.1038\/s41598-020-79570-x","article-title":"Clinically-identified C-terminal mutations in fibulin-3 are prone to misfolding and destabilization.","volume":"11","author":"Woodard","year":"2021","journal-title":"Sci Rep"},{"issue":"7","key":"eoi260053r23","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0132529","article-title":"Exome sequencing identifies a missense variant in EFEMP1 co-segregating in a family with autosomal dominant primary open-angle glaucoma.","volume":"10","author":"Mackay","year":"2015","journal-title":"PLoS One"},{"issue":"2","key":"eoi260053r24","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1002\/humu.24320","article-title":"EFEMP1 rare variants cause familial juvenile-onset open-angle glaucoma.","volume":"43","author":"Collantes","year":"2022","journal-title":"Hum Mutat"},{"issue":"1","key":"eoi260053r25","doi-asserted-by":"publisher","first-page":"30028","DOI":"10.1038\/s41598-025-14561-4","article-title":"A spectrum of cysteine mutations in fibulin-3 highlight its disulfide bonding complexity and potential to induce ER stress.","volume":"15","author":"Collier","year":"2025","journal-title":"Sci Rep"},{"issue":"31","key":"eoi260053r26","doi-asserted-by":"publisher","first-page":"22821","DOI":"10.1074\/jbc.M112.439158","article-title":"Fibulin-3, -4, and -5 are highly susceptible to proteolysis, interact with cells and heparin, and form multimers.","volume":"288","author":"Djokic","year":"2013","journal-title":"J Biol Chem"},{"issue":"2","key":"eoi260053r27","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1093\/hmg\/ddac187","article-title":"Complement factor B is critical for sub-RPE deposit accumulation in a model of Doyne honeycomb retinal dystrophy with features of age-related macular degeneration.","volume":"32","author":"Crowley","year":"2023","journal-title":"Hum Mol Genet"},{"issue":"3","key":"eoi260053r28","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1016\/j.ajo.2006.11.041","article-title":"Progression of geographic atrophy and impact of fundus autofluorescence patterns in age-related macular degeneration.","volume":"143","author":"Holz","year":"2007","journal-title":"Am J Ophthalmol"},{"issue":"4","key":"eoi260053r29","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1016\/j.ajo.2008.10.022","article-title":"Extensive macular atrophy with pseudodrusen-like appearance: a new clinical entity.","volume":"147","author":"Hamel","year":"2009","journal-title":"Am J Ophthalmol"},{"issue":"6","key":"eoi260053r30","doi-asserted-by":"publisher","first-page":"2463","DOI":"10.1167\/iovs.15-18593","article-title":"Distinct genetic risk profile of the rapidly progressing diffuse-trickling subtype of geographic atrophy in age-related macular degeneration (AMD).","volume":"57","author":"Fleckenstein","year":"2016","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"10","key":"eoi260053r31","doi-asserted-by":"publisher","first-page":"1175","DOI":"10.1016\/j.ophtha.2024.04.001","article-title":"Extensive macular atrophy with pseudodrusen-like appearance: progression kinetics and late-stage findings.","volume":"131","author":"Antropoli","year":"2024","journal-title":"Ophthalmology"}],"container-title":["JAMA Ophthalmology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamaophthalmology\/articlepdf\/2853776\/jamaophthalmology_stanton_2026_oi_260053_1788184967.9075.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T15:00:36Z","timestamp":1789052436000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamaophthalmology\/fullarticle\/2853776"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,10]]},"references-count":31,"URL":"https:\/\/doi.org\/10.1001\/jamaophthalmol.2026.3828","relation":{},"ISSN":["2168-6165"],"issn-type":[{"value":"2168-6165","type":"print"}],"subject":[],"published":{"date-parts":[[2026,9,10]]}}}