{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T13:03:10Z","timestamp":1765285390466,"version":"3.46.0"},"reference-count":43,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T00:00:00Z","timestamp":1765238400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Thames Valley and South Midlands Clinical Research Network"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Pathogenic variants in interphotoreceptor matrix proteoglycan 1 (IMPG1) have been associated with autosomal dominant and recessive retinitis pigmentosa (RP) and autosomal dominant adult vitelliform macular dystrophy (AVMD). Monoallelic pathogenic variants in IMPG2 have been linked to maculopathy and biallelic variants to RP with early onset macular atrophy. Herein we characterise the phenotypic and genotypic features of patients with IMPG1\/IMPG2 retinopathy and report novel variants. Methods: Patients with IMPG1 and IMPG2 variants and compatible phenotypes were retrospectively identified. Clinical data were obtained from reviewing the medical records. Phenotypic data included visual acuity, imaging included ultra-widefield pseudo-colour, fundus autofluorescence, and optical coherence tomography (OCT). Genetic testing was performed using next generation sequencing (NGS). Variant pathogenicity was investigated using in silico analysis (SIFT, PolyPhen-2, mutation taster, SpliceAI). The evolutionary conservation of novel missense variants was also investigated. Results: A total of 13 unrelated patients were identified: 2 (1 male; 1 female) with IMPG1 retinopathy and 11 (7 male; 4 female) with IMPG2 retinopathy. Both IMPG1 retinopathy patients were monoallelic: one patient had adult vitelliform macular dystrophy (AVMD) with drusenoid changes while the other had pattern dystrophy (PD), and they presented to clinic at age 81 and 72 years, respectively. There were 5 monoallelic IMPG2 retinopathy patients with a maculopathy phenotype, of whom 1 had PD and 4 had AVMD. The mean age of symptom onset of this group was 54.2 \u00b1 11.8 years, mean age at presentation was 54.8 \u00b1 11.5 years, and mean BCVAs were 0.15 \u00b1 0.12 logMAR OD and \u22120.01 \u00b1 0.12 logMAR OS. Six biallelic IMPG2 patients had RP with maculopathy, where the mean age of onset symptom onset was 18.4 years, mean age at examination was 68.7 years, and mean BCVAs were 1.90 logMAR OD and 1.82 logMAR OS. Variants in IMPG1 included one missense and one exon deletion. A total of 11 different IMPG2 variants were identified (4 missense, 7 truncating). A splicing defect was predicted for the c.871C&gt;A p.(Arg291Ser) missense IMPG2 variant. One IMPG1 and five IMPG2 variants were novel. Conclusions: This study describes the phenotypic spectrum of IMPG1\/IMPG2 retinopathy and six novel variants are reported. The phenotypes of PD and AVMD in monoallelic IMPG2 patients may result from haploinsufficiency, supported by the presence of truncating variants in both monoallelic and biallelic cases. The identification of novel variants expands the known genetic landscape of IMPG1 and IMPG2 retinopathies. These findings contribute to diagnostic accuracy, informed patient counselling regarding inheritance pattern, and may help guide recruitment for future therapeutic interventions.<\/jats:p>","DOI":"10.3390\/genes16121474","type":"journal-article","created":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T12:42:43Z","timestamp":1765284163000},"page":"1474","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Expanding the Genetic Spectrum in IMPG1 and IMPG2 Retinopathy"],"prefix":"10.3390","volume":"16","author":[{"given":"Saoud","family":"Al-Khuzaei","sequence":"first","affiliation":[{"name":"Oxford Eye Hospital, John Radcliffe Hospital, Oxford University Hospitals-NHS Foundation Trust, Oxford OX3 9DU, UK"},{"name":"Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neuroscience, University of Oxford, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0647-5862","authenticated-orcid":false,"given":"Ahmed K.","family":"Shalaby","sequence":"additional","affiliation":[{"name":"Oxford Eye Hospital, John Radcliffe Hospital, Oxford University Hospitals-NHS Foundation Trust, Oxford OX3 9DU, UK"},{"name":"Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neuroscience, University of Oxford, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Yu","sequence":"additional","affiliation":[{"name":"Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neuroscience, University of Oxford, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Morag","family":"Shanks","sequence":"additional","affiliation":[{"name":"Oxford Medical Genetics Laboratories, Oxford University Hospitals-NHS Foundation Trust, Oxford OX3 7LE, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Penny","family":"Clouston","sequence":"additional","affiliation":[{"name":"Oxford Medical Genetics Laboratories, Oxford University Hospitals-NHS Foundation Trust, Oxford OX3 7LE, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert E.","family":"MacLaren","sequence":"additional","affiliation":[{"name":"Oxford Eye Hospital, John Radcliffe Hospital, Oxford University Hospitals-NHS Foundation Trust, Oxford OX3 9DU, UK"},{"name":"Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neuroscience, University of Oxford, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"Halford","sequence":"additional","affiliation":[{"name":"Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neuroscience, University of Oxford, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4455-2814","authenticated-orcid":false,"given":"Samantha R.","family":"De Silva","sequence":"additional","affiliation":[{"name":"Oxford Eye Hospital, John Radcliffe Hospital, Oxford University Hospitals-NHS Foundation Trust, Oxford OX3 9DU, UK"},{"name":"Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neuroscience, University of Oxford, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7373-2665","authenticated-orcid":false,"given":"Susan M.","family":"Downes","sequence":"additional","affiliation":[{"name":"Oxford Eye Hospital, John Radcliffe Hospital, Oxford University Hospitals-NHS Foundation Trust, Oxford OX3 9DU, UK"},{"name":"Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neuroscience, University of Oxford, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.preteyeres.2017.03.003","article-title":"Unravelling the genetics of inherited retinal dystrophies: Past, present and future","volume":"59","author":"Broadgate","year":"2017","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e004015","DOI":"10.1136\/bmjopen-2013-004015","article-title":"A comparison of the causes of blindness certifications in England and Wales in working age adults (16\u201364 years), 1999\u20132000 with 2009\u20132010","volume":"4","author":"Liew","year":"2014","journal-title":"BMJ Open"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1080\/13816810.2021.1913610","article-title":"Inherited retinal diseases are the most common cause of blindness in the working-age population in Australia","volume":"42","author":"Mukhtar","year":"2021","journal-title":"Ophthalmic Genet."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Garc\u00eda Boh\u00f3rquez, B., Aller, E., Rodr\u00edguez Mu\u00f1oz, A., Jaijo, T., Garc\u00eda Garc\u00eda, G., and Mill\u00e1n, J.M. (2021). Updating the Genetic Landscape of Inherited Retinal Dystrophies. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.645600"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3939","DOI":"10.1167\/iovs.14-14129","article-title":"IMPG2-associated retinitis pigmentosa displays relatively early macular involvement","volume":"55","author":"Collin","year":"2014","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2406","DOI":"10.1016\/j.ophtha.2014.06.028","article-title":"Frequency and clinical pattern of vitelliform macular dystrophy caused by mutations of interphotoreceptor matrix IMPG1 and IMPG2 genes","volume":"121","author":"Meunier","year":"2014","journal-title":"Ophthalmology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.ajo.2023.10.002","article-title":"IMPG2-Related Maculopathy","volume":"258","author":"Birtel","year":"2024","journal-title":"Am. J. Ophthalmol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Brandl, C., Schulz, H.L., Charbel Issa, P., Birtel, J., Bergholz, R., Lange, C., Dahlke, C., Zobor, D., Weber, B.H.F., and St\u00f6hr, H. (2017). Mutations in the Genes for Interphotoreceptor Matrix Proteoglycans, IMPG1 and IMPG2, in Patients with Vitelliform Macular Lesions. Genes, 8.","DOI":"10.3390\/genes8070170"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1006\/exer.2000.0888","article-title":"SPACR in the interphotoreceptor matrix of the mouse retina: Molecular, biochemical and immunohistochemical characterization","volume":"71","author":"Lee","year":"2000","journal-title":"Exp. Eye Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/S0945-053X(99)00043-8","article-title":"Expression and characterization of the IPM 150 gene (IMPG1) product, a novel human photoreceptor cell-associated chondroitin-sulfate proteoglycan","volume":"18","author":"Kuehn","year":"1999","journal-title":"Matrix Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1006\/mcbr.1999.0161","article-title":"Molecular characterization and genomic mapping of human IPM 200, a second member of a novel family of proteoglycans","volume":"2","author":"Kuehn","year":"1999","journal-title":"Mol. Cell Biol. Res. Commun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6945","DOI":"10.1074\/jbc.275.10.6945","article-title":"SPACRCAN, a novel human interphotoreceptor matrix hyaluronan-binding proteoglycan synthesized by photoreceptors and pinealocytes","volume":"275","author":"Acharya","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0014-4835(02)00273-7","article-title":"SPACRCAN in the interphotoreceptor matrix of the mouse retina: Molecular, developmental and promoter analysis","volume":"76","author":"Chen","year":"2003","journal-title":"Exp. Eye Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4059","DOI":"10.1523\/JNEUROSCI.2994-19.2020","article-title":"Proteoglycan IMPG2 Shapes the Interphotoreceptor Matrix and Modulates Vision","volume":"40","author":"Salido","year":"2020","journal-title":"J. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/0014-4835(82)90088-4","article-title":"Proteins and glycoproteins of the bovine interphotoreceptor matrix: Composition and fractionation","volume":"34","author":"Adler","year":"1982","journal-title":"Exp. Eye Res."},{"key":"ref_16","unstructured":"Hageman, G., and Johnson, L. (1991). Progress in Retinal Research, Elsevier."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.exer.2015.02.017","article-title":"Structure and function of the interphotoreceptor matrix surrounding retinal photoreceptor cells","volume":"133","author":"Ishikawa","year":"2015","journal-title":"Exp. Eye Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/S1350-9462(02)00009-5","article-title":"Proteoglycans in retina","volume":"21","author":"Inatani","year":"2002","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1002\/cne.22773","article-title":"Cone outer segment extracellular matrix as binding domain for interphotoreceptor retinoid-binding protein","volume":"520","author":"Garlipp","year":"2012","journal-title":"J. Comp. Neurol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.actbio.2018.05.023","article-title":"Extracellular matrix component expression in human pluripotent stem cell-derived retinal organoids recapitulates retinogenesis in vivo and reveals an important role for IMPG1 and CD44 in the development of photoreceptors and interphotoreceptor matrix","volume":"74","author":"Felemban","year":"2018","journal-title":"Acta Biomater."},{"key":"ref_21","first-page":"2767","article-title":"Hyaluronan and the functional organization of the interphotoreceptor matrix","volume":"40","author":"Hollyfield","year":"1999","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"23142","DOI":"10.1074\/jbc.M401584200","article-title":"Spacrcan binding to hyaluronan and other glycosaminoglycans. Molecular and biochemical studies","volume":"279","author":"Chen","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Mitchell, B., Coulter, C., Geldenhuys, W.J., Rhodes, S., and Salido, E.M. (2022). Interphotoreceptor matrix proteoglycans IMPG1 and IMPG2 proteolyze in the SEA domain and reveal localization mutual dependency. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-19910-1"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/j.ajhg.2013.07.018","article-title":"Mutations in IMPG1 cause vitelliform macular dystrophies","volume":"93","author":"Manes","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Yuan, M., Chatterjee, S., Leys, M., Odom, J.V., and Salido, E.M. (2025). Prevalence of IMPG1 and IMPG2 Mutations Leading to Retinitis Pigmentosa or Vitelliform Macular Dystrophy in a Cohort of Patients with Inherited Retinal Dystrophies. Genes, 16.","DOI":"10.3390\/genes16010043"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1136\/jmedgenet-2020-107150","article-title":"Pathogenic variants in IMPG1 cause autosomal dominant and autosomal recessive retinitis pigmentosa","volume":"58","author":"Olivier","year":"2021","journal-title":"J. Med. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1080\/13816810.2019.1627467","article-title":"Homozygous and heterozygous retinal phenotypes in families harbouring IMPG2 mutations","volume":"40","author":"Khan","year":"2019","journal-title":"Ophthalmic Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1167\/iovs.63.1.27","article-title":"Identification of a Complex Allele in IMPG2 as a Cause of Adult-Onset Vitelliform Macular Dystrophy","volume":"63","author":"Li","year":"2022","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/j.jcrs.2004.01.014","article-title":"Visual acuity measurements","volume":"30","author":"Holladay","year":"2004","journal-title":"J. Cataract. Refract. Surg."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1080\/13816810.2020.1778736","article-title":"Next generation sequencing using phenotype-based panels for genetic testing in inherited retinal diseases","volume":"41","author":"Shah","year":"2020","journal-title":"Ophthalmic Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/ng.2892","article-title":"A general framework for estimating the relative pathogenicity of human genetic variants","volume":"46","author":"Kircher","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"eadg7492","DOI":"10.1126\/science.adg7492","article-title":"Accurate proteome-wide missense variant effect prediction with AlphaMissense","volume":"381","author":"Cheng","year":"2023","journal-title":"Science"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.cell.2018.12.015","article-title":"Predicting Splicing from Primary Sequence with Deep Learning","volume":"176","author":"Jaganathan","year":"2019","journal-title":"Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s40246-023-00451-1","article-title":"SpliceAI-visual: A free online tool to improve SpliceAI splicing variant interpretation","volume":"17","author":"Filser","year":"2023","journal-title":"Hum. Genom."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"101699","DOI":"10.1016\/j.ajoc.2022.101699","article-title":"IMPG2-associated unilateral adult onset vitelliform macular dystrophy","volume":"28","author":"Georgiou","year":"2022","journal-title":"Am. J. Ophthalmol. Case Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1097\/ICB.0000000000000824","article-title":"ADULT-ONSET VITELLIFORM MACULAR DYSTROPHY SECONDARY TO A NOVEL IMPG2 GENE VARIANT","volume":"15","author":"Shah","year":"2021","journal-title":"Retin. Cases Brief. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1001\/jamaophthalmol.2020.0666","article-title":"Association of Clinical and Genetic Heterogeneity with BEST1 Sequence Variations","volume":"138","author":"Shah","year":"2020","journal-title":"JAMA Ophthalmol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"101236","DOI":"10.1016\/j.preteyeres.2024.101236","article-title":"Central serous chorioretinopathy: An evidence-based treatment guideline","volume":"101","author":"Feenstra","year":"2024","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"100955","DOI":"10.1016\/j.preteyeres.2021.100955","article-title":"Serous business: Delineating the broad spectrum of diseases with subretinal fluid in the macula","volume":"84","author":"Boon","year":"2021","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Olivier, G., Brabet, P., Pirot, N., Broyon, M., Guillou, L., Cazevieille, C., Sar, C., Quiles, M., Sarzi, E., and Pequignot, M. (2022). SPACR Encoded by IMPG1 Is Essential for Photoreceptor Survival by Interplaying between the Interphotoreceptor Matrix and the Retinal Pigment Epithelium. Genes, 13.","DOI":"10.3390\/genes13091508"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1624","DOI":"10.1093\/hmg\/ddaa062","article-title":"Deletion of the Impg2 gene causes the degeneration of rod and cone cells in mice","volume":"29","author":"Xu","year":"2020","journal-title":"Hum. Mol. Genet."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1093\/hmg\/ddad199","article-title":"Heterogeneity in the progression of retinal pathologies in mice harboring patient mimicking Impg2 mutations","volume":"33","author":"Williams","year":"2024","journal-title":"Hum. Mol. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2409","DOI":"10.1016\/j.stemcr.2022.09.004","article-title":"Human retinal organoids harboring IMPG2 mutations exhibit a photoreceptor outer segment phenotype that models advanced retinitis pigmentosa","volume":"17","author":"Mayerl","year":"2022","journal-title":"Stem Cell Rep."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/12\/1474\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T12:59:16Z","timestamp":1765285156000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/12\/1474"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,9]]},"references-count":43,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["genes16121474"],"URL":"https:\/\/doi.org\/10.3390\/genes16121474","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,9]]}}}