{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T15:14:35Z","timestamp":1750173275214},"reference-count":25,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,8,10]],"date-time":"2017-08-10T00:00:00Z","timestamp":1502323200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,8,10]],"date-time":"2017-08-10T00:00:00Z","timestamp":1502323200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Congenital cavitary optic disc anomalies (CODA) is clinically typified by an enlarged excavation of optic disc in diverse degrees. Here, we report the clinical and genetic findings in a four-generation Chinese family with a complicated form of autosomal dominant CODA. Cardinal manifestations included bilateral excavated optic disc with multiple cilioretinal vessels emerging and bilateral retinoschisis with great variability in the range of extension and severity. Other intra-familial phenotypic diversities were also noted, including severity in retinal atrophy, onset age of visual impairment and presence of congenital nystagmus and strabismus. Genome-wide linkage analysis and fine mapping mapped a novel locus for CODA to a 34.3\u2009cM interval between D14S972 and D14S139 at 14q12-q22.1. A maximum multi-point log odds score of 3.901 was reached at D14S275. However, no mutation was identified by exome sequencing or direct sequencing of <jats:italic>PAX6<\/jats:italic> and <jats:italic>PAX2<\/jats:italic> genes, suggesting that the mutation may reside within a regulatory element. In conclusion, we find retinoschisis as a necessary consequence of optic nerve head (ONH) anomalies. The complicated phenotype observed in the family provided additional insights into the inherited ONH anomalies. Mapping of a novel locus, 14q12-q22.1, implies a new disease-causing gene and potential distinct pathogenesis for CODA.<\/jats:p>","DOI":"10.1038\/s41598-017-07730-7","type":"journal-article","created":{"date-parts":[[2017,8,4]],"date-time":"2017-08-04T13:41:04Z","timestamp":1501854064000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A large family with inherited optic disc anomalies: a correlation between a new genetic locus and complex ocular phenotypes"],"prefix":"10.1038","volume":"7","author":[{"given":"Decai","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinyuan","family":"Pan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiangdong","family":"Ji","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shun","family":"Gu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiantao","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chao","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weiyi","family":"Xia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhihua","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoli","family":"Kang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sijia","family":"Ding","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qinghuai","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xue","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fang","family":"Lu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chen","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2017,8,10]]},"reference":[{"key":"7730_CR1","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1016\/S0161-6420(89)32886-7","volume":"96","author":"MM Slusher","year":"1989","unstructured":"Slusher, M. M., Weaver, R. G. Jr., Greven, C. M., Mundorf, T. K. & Cashwell, L. F. The spectrum of cavitary optic disc anomalies in a family. Ophthalmology \n                           96, 342\u2013347 (1989).","journal-title":"Ophthalmology"},{"key":"7730_CR2","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/0039-6257(94)90155-4","volume":"39","author":"MC Brodsky","year":"1994","unstructured":"Brodsky, M. C. Congenital optic disk anomalies. Survey of ophthalmology \n                           39, 89\u2013112 (1994).","journal-title":"Survey of ophthalmology"},{"key":"7730_CR3","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1016\/j.ajo.2007.01.029","volume":"143","author":"RA Honkanen","year":"2007","unstructured":"Honkanen, R. A. et al. Familial cavitary optic disk anomalies: clinical features of a large family with examples of progressive optic nerve head cupping. American journal of ophthalmology \n                           143, 788\u2013794, doi:10.1016\/j.ajo.2007.01.029 (2007).","journal-title":"American journal of ophthalmology"},{"key":"7730_CR4","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1001\/archopht.1976.03910030183002","volume":"94","author":"J Savell","year":"1976","unstructured":"Savell, J. & Cook, J. R. Optic nerve colobomas of autosomal-dominant heredity. Archives of ophthalmology \n                           94, 395\u2013400 (1976).","journal-title":"Archives of ophthalmology"},{"key":"7730_CR5","doi-asserted-by":"publisher","first-page":"1565","DOI":"10.1086\/375555","volume":"72","author":"N Azuma","year":"2003","unstructured":"Azuma, N. et al. Mutations of the PAX6 gene detected in patients with a variety of optic-nerve malformations. American journal of human genetics \n                           72, 1565\u20131570, doi:10.1086\/375555 (2003).","journal-title":"American journal of human genetics"},{"key":"7730_CR6","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1002\/humu.22020","volume":"33","author":"M Bower","year":"2012","unstructured":"Bower, M. et al. Update of PAX2 mutations in renal coloboma syndrome and establishment of a locus-specific database. Human mutation \n                           33, 457\u2013466, doi:10.1002\/humu.22020 (2012).","journal-title":"Human mutation"},{"key":"7730_CR7","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1016\/j.ajo.2007.01.042","volume":"143","author":"JH Fingert","year":"2007","unstructured":"Fingert, J. H. et al. Familial cavitary optic disk anomalies: identification of a novel genetic locus. Am J Ophthalmol \n                           143, 795\u2013800, doi:10.1016\/j.ajo.2007.01.042 (2007).","journal-title":"Am J Ophthalmol"},{"key":"7730_CR8","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1002\/humu.22754","volume":"36","author":"RJ Hazlewood","year":"2015","unstructured":"Hazlewood, R. J. et al. Heterozygous triplication of upstream regulatory sequences leads to dysregulation of matrix metalloproteinase 19 in patients with cavitary optic disc anomaly. Hum Mutat \n                           36, 369\u2013378, doi:10.1002\/humu.22754 (2015).","journal-title":"Hum Mutat"},{"key":"7730_CR9","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1001\/archneur.1980.00500530048006","volume":"37","author":"JJ Corbett","year":"1980","unstructured":"Corbett, J. J., Savino, P. J., Schatz, N. J. & Orr, L. S. Cavitary developmental defects of the optic disc. Visual loss associated with optic pits and colobomas. Archives of neurology \n                           37, 210\u2013213 (1980).","journal-title":"Archives of neurology"},{"key":"7730_CR10","doi-asserted-by":"crossref","unstructured":"Parsa, C. F., Cheeseman, E. W., Jr., & Maumenee, I. H. Demonstration of exclusive cilioretinal vascular system supplying the retina in man: vacant discs. Transactions of the American Ophthalmological Society \n                           96, 95\u2013106; discussion 106\u2013109 (1998).","DOI":"10.1016\/S0026-0576(98)80266-3"},{"key":"7730_CR11","doi-asserted-by":"publisher","first-page":"e1005723","DOI":"10.1371\/journal.pgen.1005723","volume":"11","author":"D Vollrath","year":"2015","unstructured":"Vollrath, D. et al. Tyro3 Modulates Mertk-Associated Retinal Degeneration. PLoS Genet \n                           11, e1005723, doi:10.1371\/journal.pgen.1005723 (2015).","journal-title":"PLoS Genet"},{"key":"7730_CR12","doi-asserted-by":"publisher","first-page":"e1003040","DOI":"10.1371\/journal.pgen.1003040","volume":"8","author":"G Venturini","year":"2012","unstructured":"Venturini, G., Rose, A. M., Shah, A. Z., Bhattacharya, S. S. & Rivolta, C. CNOT3 is a modifier of PRPF31 mutations in retinitis pigmentosa with incomplete penetrance. PLoS Genet \n                           8, e1003040, doi:10.1371\/journal.pgen.1003040 (2012).","journal-title":"PLoS Genet"},{"key":"7730_CR13","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1111\/ahg.12042","volume":"78","author":"AM Rose","year":"2014","unstructured":"Rose, A. M. et al. Dominant PRPF31 mutations are hypostatic to a recessive CNOT3 polymorphism in retinitis pigmentosa: a novel phenomenon of \u201clinked trans-acting epistasis\u201d. Ann Hum Genet \n                           78, 62\u201371, doi:10.1111\/ahg.12042 (2014).","journal-title":"Ann Hum Genet"},{"key":"7730_CR14","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1136\/bjophthalmol-2014-305722","volume":"99","author":"MR Munk","year":"2015","unstructured":"Munk, M. R., Simjanoski, E., Fingert, J. H. & Jampol, L. M. Enhanced depth imaging optical coherence tomography of congenital cavitary optic disc anomaly (CODA). The British journal of ophthalmology \n                           99, 549\u2013555, doi:10.1136\/bjophthalmol-2014-305722 (2015).","journal-title":"The British journal of ophthalmology"},{"key":"7730_CR15","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1007\/s10384-009-0748-6","volume":"54","author":"LO Atchaneeyasakul","year":"2010","unstructured":"Atchaneeyasakul, L. O. et al. Mutations in the XLRS1 gene in Thai families with X-linked juvenile retinoschisis. Japanese journal of ophthalmology \n                           54, 89\u201393, doi:10.1007\/s10384-009-0748-6 (2010).","journal-title":"Japanese journal of ophthalmology"},{"key":"7730_CR16","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1136\/bjo.79.7.697","volume":"79","author":"ND George","year":"1995","unstructured":"George, N. D., Yates, J. R. & Moore, A. T. X linked retinoschisis. The British journal of ophthalmology \n                           79, 697\u2013702 (1995).","journal-title":"The British journal of ophthalmology"},{"key":"7730_CR17","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1001\/archopht.1996.01100130270007","volume":"114","author":"ND George","year":"1996","unstructured":"George, N. D., Yates, J. R. & Moore, A. T. Clinical features in affected males with X-linked retinoschisis. Archives of ophthalmology \n                           114, 274\u2013280 (1996).","journal-title":"Archives of ophthalmology"},{"key":"7730_CR18","doi-asserted-by":"publisher","first-page":"4342","DOI":"10.1167\/iovs.09-3418","volume":"50","author":"R Riveiro-Alvarez","year":"2009","unstructured":"Riveiro-Alvarez, R. et al. Correlation of genetic and clinical findings in Spanish patients with X-linked juvenile retinoschisis. Investigative ophthalmology & visual science \n                           50, 4342\u20134350, doi:10.1167\/iovs.09-3418 (2009).","journal-title":"Investigative ophthalmology & visual science"},{"key":"7730_CR19","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1007\/s10633-011-9278-x","volume":"123","author":"F Xu","year":"2011","unstructured":"Xu, F., Xiang, H., Jiang, R., Dong, F. & Sui, R. Phenotypic expression of X-linked retinoschisis in Chinese families with mutations in the RS1 gene. Documenta ophthalmologica. Advances in ophthalmology \n                           123, 21\u201327, doi:10.1007\/s10633-011-9278-x (2011).","journal-title":"Documenta ophthalmologica. Advances in ophthalmology"},{"key":"7730_CR20","doi-asserted-by":"publisher","first-page":"1255","DOI":"10.1007\/s00417-011-1668-y","volume":"249","author":"M Zhao","year":"2011","unstructured":"Zhao, M. & Li, X. Macular retinoschisis associated with normal tension glaucoma. Graefe\u2019s archive for clinical and experimental ophthalmology\u2009=\u2009Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie \n                           249, 1255\u20131258, doi:10.1007\/s00417-011-1668-y (2011).","journal-title":"Graefe\u2019s archive for clinical and experimental ophthalmology\u2009=\u2009Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie"},{"key":"7730_CR21","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1001\/archopht.123.2.270","volume":"123","author":"DA Hollander","year":"2005","unstructured":"Hollander, D. A., Barricks, M. E., Duncan, J. L. & Irvine, A. R. Macular schisis detachment associated with angle-closure glaucoma. Archives of ophthalmology \n                           123, 270\u2013272, doi:10.1001\/archopht.123.2.270 (2005).","journal-title":"Archives of ophthalmology"},{"key":"7730_CR22","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1038\/ng0495-358","volume":"9","author":"P Sanyanusin","year":"1995","unstructured":"Sanyanusin, P. et al. Mutation of the PAX2 gene in a family with optic nerve colobomas, renal anomalies and vesicoureteral reflux. Nature genetics \n                           9, 358\u2013364, doi:10.1038\/ng0495-358 (1995).","journal-title":"Nature genetics"},{"key":"7730_CR23","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1136\/bjo.83.6.723","volume":"83","author":"S Nishina","year":"1999","unstructured":"Nishina, S. et al. PAX6 expression in the developing human eye. The British journal of ophthalmology \n                           83, 723\u2013727 (1999).","journal-title":"The British journal of ophthalmology"},{"key":"7730_CR24","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1046\/j.1365-2443.1996.11011.x","volume":"1","author":"WJ Gehring","year":"1996","unstructured":"Gehring, W. J. The master control gene for morphogenesis and evolution of the eye. Genes to cells: devoted to molecular & cellular mechanisms \n                           1, 11\u201315 (1996).","journal-title":"Genes to cells: devoted to molecular & cellular mechanisms"},{"key":"7730_CR25","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1038\/ng786","volume":"30","author":"GR Abecasis","year":"2002","unstructured":"Abecasis, G. R., Cherny, S. S., Cookson, W. O. & Cardon, L. R. Merlin\u2013rapid analysis of dense genetic maps using sparse gene flow trees. Nature genetics \n                           30, 97\u2013101, doi:10.1038\/ng786 (2002).","journal-title":"Nature genetics"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-07730-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-07730-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-07730-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T08:27:42Z","timestamp":1671784062000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-07730-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,8,10]]},"references-count":25,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["7730"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-07730-7","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,8,10]]},"assertion":[{"value":"18 October 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 July 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 August 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"7799"}}