{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T17:28:37Z","timestamp":1790270917703,"version":"4.1.0"},"reference-count":51,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2024,7,23]],"date-time":"2024-07-23T00:00:00Z","timestamp":1721692800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>We present two children aged 3 and 5 years who share identical TYR genotype, yet exhibit contrasting phenotypic manifestations in terms of eye, skin, and hair coloration. The patients are heterozygous for TYR c.1A&gt;G, p. (Met1?), which is pathogenic, and homozygous for TYR c.1205G&gt;A, p. (Arg402Gln), which is classified as a risk factor. The children manifested diminished visual acuity, nystagmus, and foveal hypoplasia. The first patient presented with hypopigmentation of the skin, hair, and ocular tissues, while the second patient presented with hypopigmentation of the skin, hair, retinal pigment epithelium, and choroid with dark brown irises. Furthermore, the brown-eyed subject presented astigmatic refractive error and both global and local stereopsis capabilities, contrasting with the presentation of hypermetropia, strabismus, and the absence of stereopsis in the blue-eyed individual. Herein, we propose a genotype\u2013phenotype correlation model to elucidate the diverse clinical presentations stemming from biallelic and triallelic pathogenic variants in TYR, establishing a link between the residual tyrosinase activity and resultant phenotypes. According to our proposed model, the severity of TYR variants correlates with distinct albino phenotypes. Our findings propose the potential association between reduced pigmentation levels in ocular tissues and binocular functions, suggesting pigmentation as a possible independent variable influencing the onset of strabismus\u2014an association unreported until now in the existing literature.<\/jats:p>","DOI":"10.3390\/diagnostics14151583","type":"journal-article","created":{"date-parts":[[2024,7,23]],"date-time":"2024-07-23T11:40:36Z","timestamp":1721734836000},"page":"1583","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Genotype\u2013Phenotype Correlation Model for the Spectrum of TYR-Associated Albinism"],"prefix":"10.3390","volume":"14","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":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"16576","DOI":"10.1038\/s41598-019-51768-8","article-title":"Clinical and genetic variability in children with partial albinism","volume":"9","author":"Campbell","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"101091","DOI":"10.1016\/j.preteyeres.2022.101091","article-title":"The retinal pigmentation pathway in human albinism: Not so black and white","volume":"91","author":"Bakker","year":"2022","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Chan, H.W., Schiff, E.R., Tailor, V.K., Malka, S., Neveu, M.M., Theodorou, M., and Moosajee, M. (2021). Prospective Study of the Phenotypic and Mutational Spectrum of Ocular Albinism and Oculocutaneous Albinism. Genes, 12.","DOI":"10.3390\/genes12040508"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1038\/jhg.2010.126","article-title":"Genotype\u2013phenotype associations and human eye color","volume":"56","author":"White","year":"2011","journal-title":"J. Hum. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1111\/j.1600-0749.2006.00318.x","article-title":"The other pigment cell: Specification and development of the pigmented epithelium of the vertebrate eye","volume":"19","author":"Bharti","year":"2006","journal-title":"Pigment Cell Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1523\/JNEUROSCI.01-11-01193.1981","article-title":"The distribution of melanin in the developing optic cup and stalk and its relation to cellular degeneration","volume":"1","author":"Strongin","year":"1981","journal-title":"J. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/1750-1172-2-43","article-title":"Oculocutaneous albinism","volume":"2","author":"Ek","year":"2007","journal-title":"Orphanet. J. Rare. Dis."},{"key":"ref_8","unstructured":"Hayashi, M., and Suzuki, T. (2024, May 17). Oculocutaneous Albinism Type 4, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK1510\/."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1590","DOI":"10.1002\/ajmg.a.32939","article-title":"Oculocutaneous albinism spectrum","volume":"149A","author":"Chiang","year":"2009","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e240208","DOI":"10.1136\/bcr-2020-240208","article-title":"Foveal avascular zone in oculocutaneous albinism","volume":"14","author":"Mansour","year":"2021","journal-title":"BMJ Case. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1953","DOI":"10.1016\/j.ophtha.2018.08.003","article-title":"The Phenotypic Spectrum of Albinism","volume":"125","author":"Kruijt","year":"2018","journal-title":"Ophthalmology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1016\/j.ophtha.2011.01.028","article-title":"Structural grading of foveal hypoplasia using spectral-domain optical coherence tomography a predictor of visual acuity?","volume":"118","author":"Thomas","year":"2011","journal-title":"Ophthalmology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1093\/hmg\/3.suppl_1.1469","article-title":"Molecular genetics of oculocutaneous albinism","volume":"3","author":"Spritz","year":"1994","journal-title":"Hum. Molec. Genet."},{"key":"ref_14","unstructured":"(2024, May 18). * 606933, TYROSINASE; TYR. Available online: https:\/\/www.omim.org\/entry\/606933#45."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1038\/jhg.2016.123","article-title":"Clinical evaluation and molecular screening of a large consecutive series of albino patients","volume":"62","author":"Mauri","year":"2017","journal-title":"J. Hum. Genet."},{"key":"ref_16","unstructured":"(2024, May 17). The Human Gene Mutation Database at the Institute of Medical Genetics in Cardiff. Available online: https:\/\/www.hgmd.cf.ac.uk\/ac\/index.php."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2442","DOI":"10.1038\/jid.2008.109","article-title":"Comprehensive analysis of oculocutaneous albinism among non-Hispanic caucasians shows that OCA1 is the most prevalent OCA type","volume":"128","author":"Hutton","year":"2008","journal-title":"J. Investig. Dermatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1111\/j.1755-148X.2008.00496.x","article-title":"Molecular diagnosis of oculocutaneous albinism: New mutations in the OCA1-4 genes and practical aspects","volume":"21","author":"Rooryck","year":"2008","journal-title":"Pigment Cell Melanoma Res."},{"key":"ref_19","unstructured":"Lewis, R.A. (2024, May 16). Oculocutaneous Albinism Type 1\u2014Retired Chapter, for Historical Reference Only, Available online: https:\/\/pubmed.ncbi.nlm.nih.gov\/20301345\/."},{"key":"ref_20","unstructured":"(2024, May 17). ClinVar. NM_000372.5(TYR):c.1A>G (p.Met1Val), Available online: https:\/\/www.ncbi.nlm.nih.gov\/clinvar\/variation\/3807\/."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/0009-8981(94)90131-7","article-title":"Initiation codon mutation of the tyrosinase gene as a cause of human albinism","volume":"227","author":"Breimer","year":"1994","journal-title":"Clin. Chim. Acta"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1007\/s00439-003-0998-1","article-title":"Tyrosinase gene mutations in oculocutaneous albinism 1 (OCA1): Definition of the phenotype","volume":"113","author":"King","year":"2003","journal-title":"Hum. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1167\/iovs.08-2639","article-title":"Birth prevalence and mutation spectrum in Danish patients with autosomal recessive albinism","volume":"50","author":"Ek","year":"2009","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1038\/ejhg.2017.44","article-title":"Development and clinical utility of a novel diagnostic nystagmus gene panel using targeted next-generation sequencing","volume":"25","author":"Thomas","year":"2017","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1111\/pcmr.12651","article-title":"Lessons of a day hospital: Comprehensive assessment of patients with albinism in a European setting","volume":"31","author":"Marti","year":"2018","journal-title":"Pigment Cell Melanoma Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1111\/pcmr.12790","article-title":"Comprehensive analysis of spectral distribution of a large cohort of Chinese patients with non-syndromic oculocutaneous albinism facilitates genetic diagnosis","volume":"32","author":"Zhong","year":"2019","journal-title":"Pigment Cell Melanoma Res."},{"key":"ref_27","unstructured":"GnomAD Browser (2024, May 18). TYR Tyrosinase. Available online: https:\/\/gnomad.broadinstitute.org\/gene\/ENSG00000077498?dataset=gnomad_r4."},{"key":"ref_28","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."},{"key":"ref_29","unstructured":"(2024, May 17). ClinVar. NM_000372.5(TYR):c.1205G>A (p.Arg402Gln), Available online: https:\/\/www.ncbi.nlm.nih.gov\/clinvar\/variation\/3779\/."},{"key":"ref_30","unstructured":"GnomAD Browser (2024, May 20). SNV: 11-89284793-G-A (GRCh38). Available online: https:\/\/gnomad.broadinstitute.org\/variant\/11-89284793-G-A?dataset=gnomad_r4."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1136\/bjophthalmol-2018-312729","article-title":"Mild form of oculocutaneous albinism type 1: Phenotypic analysis of compound heterozygous patients with the R402Q variant of the TYR gene","volume":"103","author":"Lasseaux","year":"2019","journal-title":"Br. J. Ophthalmol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/ng0195-92","article-title":"Autosomal recessive ocular albinism associated with a functionally significant tyrosinase gene polymorphism","volume":"9","author":"Fukai","year":"1995","journal-title":"Nat. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2739","DOI":"10.1002\/ajmg.a.33128","article-title":"Evidence suggesting digenic inheritance of Waardenburg syndrome type II with ocular albinism","volume":"149A","author":"Chiang","year":"2009","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1167\/iovs.07-0791","article-title":"A comprehensive genetic study of autosomal recessive ocular albinism in Caucasian patients","volume":"49","author":"Hutton","year":"2008","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1002\/humu.22315","article-title":"DNA variations in oculocutaneous albinism: An updated mutation list and current outstanding issues in molecular diagnostics","volume":"34","author":"Simeonov","year":"2013","journal-title":"Hum. Mutat."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1002\/ajmg.a.32654","article-title":"The R402Q tyrosinase variant does not cause autosomal recessive ocular albinism","volume":"149A","author":"Oetting","year":"2009","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1001\/archderm.1988.01670060015008","article-title":"The validity and practicality of sun-reactive skin types I through VI","volume":"124","author":"Fitzpatrick","year":"1988","journal-title":"Arch. Dermatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1086\/510885","article-title":"A three-single-nucleotide polymorphism haplotype in intron 1 of OCA2 explains most human eye-color variation","volume":"80","author":"Duffy","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/j.ajhg.2007.10.003","article-title":"Three genome-wide association studies and a linkage analysis identify HERC2 as a human iris color gene","volume":"82","author":"Kayser","year":"2008","journal-title":"Am. J. Hum. Genet."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.ajhg.2007.11.005","article-title":"A Single SNP in an Evolutionary Conserved Region within Intron 86 of the HERC2 Gene Determines Human Blue-Brown Eye Color","volume":"82","author":"Sturm","year":"2008","journal-title":"Am. J. Hum. Genet."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Brancato, D., Coniglio, E., Bruno, F., Agostini, V., Saccone, S., and Federico, C. (2023). Forensic DNA Phenotyping: Genes and Genetic Variants for Eye Color Prediction. Genes, 14.","DOI":"10.3390\/genes14081604"},{"key":"ref_42","first-page":"103","article-title":"A polymorphism of the human tyrosinase gene is associated with temperature-sensitive enzymatic activity","volume":"1","author":"Tripathi","year":"1991","journal-title":"Gene Expr."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1042\/bj3550259","article-title":"The molecular basis of oculocutaneous albinism type 1 (OCA1): Sorting failure and degradation of mutant tyrosinases results in a lack of pigmentation","volume":"355","author":"Toyofuku","year":"2001","journal-title":"Biochem. J."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1111\/pcmr.12253","article-title":"Molecular analysis of common polymorphisms within the human Tyrosinase locus and genetic association with pigmentation traits","volume":"27","author":"Jagirdar","year":"2014","journal-title":"Pigment Cell Melanoma Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"S14","DOI":"10.1016\/S0140-6736(15)60329-4","article-title":"Retinal development in albinism: A prospective study using optical coherence tomography in infants and young children","volume":"385","author":"Lee","year":"2015","journal-title":"Lancet"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1167\/tvst.10.6.22","article-title":"Examining whether AOSLO-based foveal cone metrics in achromatopsia and albinism are representative of foveal cone structure","volume":"10","author":"Litts","year":"2021","journal-title":"Transl. Vis. Sci. Technol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/eye.1998.137","article-title":"The retinal pigment epithelium as a developmental regulator of the neural retina","volume":"12","author":"Jeffery","year":"1998","journal-title":"Eye"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1136\/jmedgenet-2017-104540","article-title":"Frequent hypomorphic alleles account for a significant fraction of ABCA4 disease and distinguish it from age-related macular degeneration","volume":"54","author":"Zernant","year":"2017","journal-title":"J. Med. Genet."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1016\/j.ophtha.2024.01.035","article-title":"A Retrospective Longitudinal Study of 460 Patients with ABCA4-Associated Retinal Disease","volume":"131","author":"Fenner","year":"2024","journal-title":"Ophthalmology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.1038\/s41436-018-0420-y","article-title":"ABCA4-associated disease as a model for missing heritability in autosomal recessive disorders: Novel noncoding splice, cis-regulatory, structural, and recurrent hypomorphic variants","volume":"21","author":"Bauwens","year":"2019","journal-title":"Genet. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e156154","DOI":"10.1172\/jci.insight.156154","article-title":"A genotype-phenotype correlation matrix for ABCA4 disease based on long-term prognostic outcomes","volume":"7","author":"Lee","year":"2022","journal-title":"JCI Insight"}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/14\/15\/1583\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:21:35Z","timestamp":1760109695000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/14\/15\/1583"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,23]]},"references-count":51,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2024,8]]}},"alternative-id":["diagnostics14151583"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics14151583","relation":{},"ISSN":["2075-4418"],"issn-type":[{"value":"2075-4418","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,23]]}}}