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Med."],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    We combined deep phenotype data and whole-genome sequencing results from the UK 100,000 Genomes Project (100KGP) to characterize the genetic spectrum of infantile nystagmus and albinism, and to explore genotype\u2013phenotype correlations in this cohort. Participants were enrolled in the study based on the clinical codes for albinism or infantile nystagmus. Whole genome sequencing data was retrieved and variants in known nystagmus\/albinism genes (PanelApp R39 panel) were analysed alongside genome-wide findings. We ascertained 473 affected individuals (388 families). Positive genetic findings were obtained in 218 participants (46%), including 176 (37%) with definitive diagnoses. Pathogenic variants were found in 16 of 38 panel genes, most commonly in\n                    <jats:italic>TYR<\/jats:italic>\n                    (56 families) and\n                    <jats:italic>OCA2<\/jats:italic>\n                    (21 families). Recurrent variants (24% of 103 different variants) were identified in six genes. An additional 36 off-panel genes accounted for diagnoses in 45 families, including four dual genetic diagnoses in three families. Phenotypically, refractive errors and foveal hypoplasia-related diagnoses were significantly enriched (odds ratio ~2.8 for refractive disorders). Strabismus and neurodevelopmental features were also over-represented in the cohort. We show that whole-genome sequencing provided a high diagnostic yield in infantile nystagmus\/albinism and uncovered a broad allelic spectrum. Integrating comprehensive phenotype data identified distinct genotype\u2013phenotype relationships.\n                  <\/jats:p>","DOI":"10.1038\/s41525-026-00580-1","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:05:16Z","timestamp":1779235516000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Whole-genome sequencing uncovers diverse genetic causes and phenotypic signatures in infantile nystagmus and albinism"],"prefix":"10.1038","volume":"11","author":[{"given":"Mahmoud R.","family":"Fassad","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pradeep C.","family":"Vasudevan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Barwell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gail DE","family":"Maconachie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Savita","family":"Madhusudhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Hunt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Gottlob","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariya","family":"Moosajee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar A.","family":"Mahroo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew R.","family":"Webster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Michaelides","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mervyn G.","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,20]]},"reference":[{"key":"580_CR1","unstructured":"Thomas, M. G., Maconachie, G., Hisaund, M. & Gottlob, I. FRMD7-Related Infantile Nystagmus. In GeneReviews\u00ae [Internet] (eds Adam, M. P. et al.) (2009). [Updated 2018 Aug 16]. Seattle (WA):University of Washington, Seattle; 1993-2026. Available from: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK3822\/."},{"key":"580_CR2","unstructured":"Thomas, M. G., Zippin, J. & Brooks, B. P. Oculocutaneous Albinism and Ocular Albinism Overview. In GeneReviews\u00ae [Internet] (eds Adam M. P. et al.) (2003) Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK590568\/."},{"key":"580_CR3","doi-asserted-by":"publisher","first-page":"506","DOI":"10.1111\/aos.14354","volume":"98","author":"K Hvid","year":"2020","unstructured":"Hvid, K. et al. Prevalence and causes of infantile nystagmus in a large population-based Danish cohort. Acta Ophthalmol. 98, 506\u2013513 (2020).","journal-title":"Acta Ophthalmol."},{"key":"580_CR4","doi-asserted-by":"publisher","first-page":"5201","DOI":"10.1167\/iovs.09-3486","volume":"50","author":"N Sarvananthan","year":"2009","unstructured":"Sarvananthan, N. et al. The prevalence of nystagmus: the Leicestershire nystagmus survey. Invest Ophthalmol. Vis. Sci. 50, 5201\u20135206 (2009).","journal-title":"Invest Ophthalmol. Vis. Sci."},{"key":"580_CR5","doi-asserted-by":"publisher","first-page":"766","DOI":"10.1038\/s41433-023-02771-x","volume":"38","author":"JG Rosenberg","year":"2024","unstructured":"Rosenberg, J. G. et al. Nystagmus in children with primary brain tumours in Denmark between 2007 and 2017. Eye (Lond.) 38, 766\u2013772 (2024).","journal-title":"Eye (Lond.)"},{"key":"580_CR6","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1161\/CIRCGENETICS.113.000578","volume":"7","author":"JR Golbus","year":"2014","unstructured":"Golbus, J. R. et al. Targeted analysis of whole genome sequence data to diagnose genetic cardiomyopathy. Circ. Cardiovasc Genet. 7, 751\u2013759 (2014).","journal-title":"Circ. Cardiovasc Genet."},{"key":"580_CR7","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1002\/uog.24911","volume":"60","author":"E Westenius","year":"2022","unstructured":"Westenius, E., Sahlin, E., Conner, P., Lindstrand, A. & Iwarsson, E. Diagnostic yield using whole-genome sequencing and in-silico panel of 281 genes associated with non-immune hydrops fetalis in clinical setting. Ultrasound Obstet. Gynecol. 60, 487\u2013493 (2022).","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"580_CR8","doi-asserted-by":"publisher","first-page":"1868","DOI":"10.1056\/NEJMoa2035790","volume":"385","author":"GPP Investigators","year":"2021","unstructured":"Investigators, G. P. P. et al. 100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care - Preliminary Report. N. Engl. J. Med. 385, 1868\u20131880 (2021).","journal-title":"N. Engl. J. Med."},{"key":"580_CR9","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1016\/j.jaapos.2023.07.007","volume":"27","author":"KM Cavuoto","year":"2023","unstructured":"Cavuoto, K. M. et al. Genetic testing for infantile nystagmus syndrome with or without associated findings. J. AAPOS. 27, 259\u2013264 (2023).","journal-title":"J. AAPOS."},{"key":"580_CR10","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1038\/ejhg.2017.44","volume":"25","author":"MG Thomas","year":"2017","unstructured":"Thomas, M. G., Maconachie, G., Sheth, V., McLean, R. J. & Gottlob, I. Development and clinical utility of a novel diagnostic nystagmus gene panel using targeted next-generation sequencing. Eur. J. Hum. Genet. 25, 725\u2013734 (2017).","journal-title":"Eur. J. Hum. 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Infantile nystagmus without overt eye abnormality: Early features and neuro-ophthalmological diagnosis. Dev. Med Child Neurol. 64, 1532\u20131538 (2022).","journal-title":"Dev. Med Child Neurol."},{"key":"580_CR17","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1080\/13816810.2016.1266667","volume":"38","author":"M Bertsch","year":"2017","unstructured":"Bertsch, M., Floyd, M., Kehoe, T., Pfeifer, W. & Drack, A. V. The clinical evaluation of infantile nystagmus: What to do first and why. Ophthalmic Genet. 38, 22\u201333 (2017).","journal-title":"Ophthalmic Genet."},{"key":"580_CR18","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1167\/iovs.66.4.39","volume":"66","author":"X Gong","year":"2025","unstructured":"Gong, X. et al. Clinical Spectrum and Molecular Characteristics of Inherited Ocular Diseases in a Cohort of Pediatric Patients With Infantile Nystagmus Syndrome. Invest Ophthalmol. Vis. Sci. 66, 39 (2025).","journal-title":"Invest Ophthalmol. Vis. 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De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome. Nature 632, 832\u2013840 (2024).","journal-title":"Nature"},{"key":"580_CR22","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1038\/s41588-025-02451-4","volume":"58","author":"M Quinodoz","year":"2026","unstructured":"Quinodoz, M. et al. De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa. Nat. Genet. 58, 169\u2013179 (2026).","journal-title":"Nat. Genet."},{"key":"580_CR23","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-024-03148-3","volume":"19","author":"Y Liu","year":"2024","unstructured":"Liu, Y. et al. Dual rare genetic diseases in five pediatric patients: insights from next-generation diagnostic methods. Orphanet J. Rare Dis. 19, 159 (2024).","journal-title":"Orphanet J. Rare Dis."},{"key":"580_CR24","doi-asserted-by":"publisher","unstructured":"Spedicati, B. et al. 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Genet Med. 17, 405\u2013424 (2015).","journal-title":"Genet Med."}],"container-title":["npj Genomic Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41525-026-00580-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41525-026-00580-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41525-026-00580-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,9]],"date-time":"2026-08-09T23:10:06Z","timestamp":1786317006000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41525-026-00580-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,20]]},"references-count":28,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["580"],"URL":"https:\/\/doi.org\/10.1038\/s41525-026-00580-1","relation":{},"ISSN":["2056-7944"],"issn-type":[{"value":"2056-7944","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,20]]},"assertion":[{"value":"30 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 May 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 May 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"43"}}