{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:21:50Z","timestamp":1760149310623,"version":"build-2065373602"},"reference-count":26,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T00:00:00Z","timestamp":1690243200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pathogenic variants in IMPDH1 are associated with autosomal dominant retinitis pigmentosa 10 (RP10), and Leber congenital amaurosis 11. This case report of a 13-year-old girl with Down\u2019s syndrome and keratoglobus is aimed at linking the novel variant IMPDH1 c.134A&gt;G, p.(Tyr45Cys), a variant of uncertain significance, to a clinical phenotype and to provide grounds for the objective assignment of its benign features. RP10 is characterized by the early onset and rapid progression of ocular symptoms, beginning with nyctalopia in childhood, accompanied by typical RP fundus changes. As evidenced via thorough clinical examination and testing, none of the RP10 characteristics were present in our patient. On the contrary, our patient who was heterozygous for IMPDH1 c.134A&gt;G, p.(Tyr45Cys) showed no signs of peripheral retinal dystrophy, and did not manifest any disease characteristics typical of the IMPDH1 gene mutation. Consequently, we conclude that the variant did not contribute to the phenotype. According to standards and guidelines for the interpretation of sequence variants, IMPDH1 c.134A&gt;G, p.(Tyr45Cys) revealed likely benign features.<\/jats:p>","DOI":"10.3390\/ijms241511889","type":"journal-article","created":{"date-parts":[[2023,7,26]],"date-time":"2023-07-26T00:45:02Z","timestamp":1690332302000},"page":"11889","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel Variant IMPDH1 c.134A&gt;G, p.(Tyr45Cys): Phenotype\u2013Genotype Correlation Revealed Likely Benign Clinical Significance"],"prefix":"10.3390","volume":"24","author":[{"given":"Mirjana","family":"Bjelo\u0161","sequence":"first","affiliation":[{"name":"University Eye Department, Reference Center of the Ministry of Health of the Republic of Croatia for Inherited Retinal Dystrophies, Reference Center of the Ministry of Health of the Republic of Croatia for Pediatric Ophthalmology and Strabismus, University Hospital \u201cSveti Duh\u201d, 10000 Zagreb, Croatia"},{"name":"Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia"},{"name":"Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3041-4186","authenticated-orcid":false,"given":"Ana","family":"\u0106uri\u0107","sequence":"additional","affiliation":[{"name":"University Eye Department, Reference Center of the Ministry of Health of the Republic of Croatia for Inherited Retinal Dystrophies, Reference Center of the Ministry of Health of the Republic of Croatia for Pediatric Ophthalmology and Strabismus, University Hospital \u201cSveti Duh\u201d, 10000 Zagreb, Croatia"},{"name":"Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mladen","family":"Bu\u0161i\u0107","sequence":"additional","affiliation":[{"name":"University Eye Department, Reference Center of the Ministry of Health of the Republic of Croatia for Inherited Retinal Dystrophies, Reference Center of the Ministry of Health of the Republic of Croatia for Pediatric Ophthalmology and Strabismus, University Hospital \u201cSveti Duh\u201d, 10000 Zagreb, Croatia"},{"name":"Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia"},{"name":"Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benedict","family":"Rak","sequence":"additional","affiliation":[{"name":"University Eye Department, Reference Center of the Ministry of Health of the Republic of Croatia for Inherited Retinal Dystrophies, Reference Center of the Ministry of Health of the Republic of Croatia for Pediatric Ophthalmology and Strabismus, University Hospital \u201cSveti Duh\u201d, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Biljana","family":"Kuzmanovi\u0107 Elabjer","sequence":"additional","affiliation":[{"name":"University Eye Department, Reference Center of the Ministry of Health of the Republic of Croatia for Inherited Retinal Dystrophies, Reference Center of the Ministry of Health of the Republic of Croatia for Pediatric Ophthalmology and Strabismus, University Hospital \u201cSveti Duh\u201d, 10000 Zagreb, Croatia"},{"name":"Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia"},{"name":"Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leon","family":"Markovi\u0107","sequence":"additional","affiliation":[{"name":"University Eye Department, Reference Center of the Ministry of Health of the Republic of Croatia for Inherited Retinal Dystrophies, Reference Center of the Ministry of Health of the Republic of Croatia for Pediatric Ophthalmology and Strabismus, University Hospital \u201cSveti Duh\u201d, 10000 Zagreb, Croatia"},{"name":"Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,25]]},"reference":[{"key":"ref_1","unstructured":"(2023, May 21). IMP DEHYDROGENASE 1; IMPDH1. Available online: https:\/\/www.omim.org\/entry\/146690."},{"key":"ref_2","unstructured":"(2023, May 21). RETINITIS PIGMENTOSA 10; RP10. Available online: https:\/\/www.omim.org\/entry\/180105146690."},{"key":"ref_3","unstructured":"(2023, May 21). LEBER CONGENITAL AMAUROSIS 11; LCA11. Available online: https:\/\/www.omim.org\/entry\/613837."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1093\/jlb\/lsx038","article-title":"The known unknown: The challenges of genetic variants of uncertain significance in clinical practice","volume":"4","year":"2017","journal-title":"J. Law. Biosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1097\/MOP.0000000000000690","article-title":"Retinitis pigmentosa: Recent advances and future directions in diagnosis and management","volume":"30","author":"Fahim","year":"2018","journal-title":"Curr. Opin. Pediatr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3754","DOI":"10.1167\/iovs.06-0207","article-title":"Why do mutations in the ubiquitously expressed housekeeping gene IMPDH1 cause retina-specific photoreceptor degeneration?","volume":"47","author":"Bowne","year":"2006","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/S0968-0004(96)30046-7","article-title":"The structure of a domain common to archaebacteria and the homocystinuria disease protein","volume":"22","author":"Bateman","year":"1997","journal-title":"Trends. Biochem. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/s12013-021-00973-2","article-title":"Terminal Peptide Extensions Augment the Retinal IMPDH1 Catalytic Activity and Attenuate the ATP-induced Fibrillation Events","volume":"79","author":"Andashti","year":"2021","journal-title":"Cell. Biochem. Biophys."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1093\/hmg\/11.5.559","article-title":"Mutations in the inosine monophosphate dehydrogenase 1 gene (IMPDH1) cause the RP10 form of autosomal dominant retinitis pigmentosa","volume":"11","author":"Bowne","year":"2002","journal-title":"Hum. Mol. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1735","DOI":"10.1167\/iovs.04-1197","article-title":"Screen of the IMPDH1 gene among patients with dominant retinitis pigmentosa and clinical features associated with the most common mutation, Asp226Asn","volume":"46","author":"Wada","year":"2005","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1167\/iovs.05-0868","article-title":"Spectrum and frequency of mutations in IMPDH1 associated with autosomal dominant retinitis pigmentosa and leber congenital amaurosis","volume":"47","author":"Bowne","year":"2006","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1093\/hmg\/11.5.547","article-title":"Identification of an IMPDH1 mutation in autosomal dominant retinitis pigmentosa (RP10) revealed following comparative microarray analysis of transcripts derived from retinas of wild-type and Rho\u2212\/\u2212 mice","volume":"11","author":"Kennan","year":"2002","journal-title":"Hum. Mol. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"8297","DOI":"10.1167\/iovs.15-17104","article-title":"Genotype and Phenotype Studies in Autosomal Dominant Retinitis Pigmentosa (adRP) of the French Canadian Founder Population","volume":"56","author":"Coussa","year":"2015","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_14","unstructured":"(2023, May 18). The Human Gene Mutation Database. Available online: http:\/\/www.hgmd.cf.ac.uk\/ac\/index.php."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1038\/s41598-018-38007-2","article-title":"Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy","volume":"9","author":"Jespersgaard","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_16","unstructured":"(2023, May 22). Genome Aggregation Database (gnomAD). Available online: https:\/\/gnomad.broadinstitute.org\/variant\/7-128049822-T-C?dataset=gnomad_r2_1."},{"key":"ref_17","unstructured":"(2023, May 21). Bravo. Available online: https:\/\/bravo.sph.umich.edu\/freeze8\/hg38\/."},{"key":"ref_18","unstructured":"(2023, May 19). University of California Santa Cruz Genomics Institute Genome Browser. Available online: https:\/\/genome.ucsc.edu."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Donato, L., Alibrandi, S., Scimone, C., Rinaldi, C., Dascola, A., Calamuneri, A., D\u2019Angelo, R., and Sidoti, A. (2022). The impact of modifier genes on cone-rod dystrophy heterogeneity: An explorative familial pilot study and a hypothesis on neurotransmission impairment. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0278857"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Donato, L., Scimone, C., Alibrandi, S., Scalinci, S.Z., Rinaldi, C., D\u2019Angelo, R., and Sidoti, A. (2022). Epitranscriptome Analysis of Oxidative Stressed Retinal Epithelial Cells Depicted a Possible RNA Editing Landscape of Retinal Degeneration. Antioxidants, 11.","DOI":"10.3390\/antiox11101967"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1038\/ng0593-54","article-title":"Localization of an autosomal dominant retinitis pigmentosa gene to chromosome 7q","volume":"4","author":"Jordan","year":"1993","journal-title":"Nat. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1038\/eye.2013.130","article-title":"Keratoglobus","volume":"27","author":"Wallang","year":"2013","journal-title":"Eye"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1186\/s13023-020-01512-7","article-title":"Multi-level consistent changes of the ECM pathway identified in a typical keratoconus twin\u2019s family by multi-omics analysis","volume":"15","author":"Hao","year":"2020","journal-title":"Orphanet. J. Rare Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1002\/ar.a.10126","article-title":"Collagen type VI expression during cardiac development and in human fetuses with trisomy 21","volume":"275A","author":"Groot","year":"2003","journal-title":"Anat. Rec."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"25158414221101718","DOI":"10.1177\/25158414221101718","article-title":"Down syndrome: A review of ocular manifestations","volume":"14","author":"Haseeb","year":"2022","journal-title":"Ther. Adv. Ophthalmol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/15\/11889\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:18:27Z","timestamp":1760127507000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/15\/11889"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,25]]},"references-count":26,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2023,8]]}},"alternative-id":["ijms241511889"],"URL":"https:\/\/doi.org\/10.3390\/ijms241511889","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2023,7,25]]}}}