{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T01:06:44Z","timestamp":1791594404988,"version":"4.3.4"},"reference-count":22,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2020,7,15]],"date-time":"2020-07-15T00:00:00Z","timestamp":1594771200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,7,15]],"date-time":"2020-07-15T00:00:00Z","timestamp":1594771200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","award":["DIMEOs"],"award-info":[{"award-number":["DIMEOs"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Calcif Tissue Int"],"published-print":{"date-parts":[[2020,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>\nConnective tissue diseases, including osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS), exhibit a high degree of clinical and genetic heterogeneity. We report two sisters with blue sclerae, joint hypermobility and hearing loss. Whole-exome sequencing identified two compound heterozygous <jats:italic>ZNF469<\/jats:italic> loss-of-function mutations due to a frameshift. Since these findings indicate the presence of brittle cornea syndrome (BCS), we performed ocular optical coherence tomography (OCT) and pachymetry, which revealed a moderate decrease in corneal thickness. While only one traumatic fracture was observed in each of the patients, a detailed skeletal assessment indicated no specific patterns of bone mass and microstructure reduction as well as normal bone turnover markers. Taken together, our findings point to a mild form of brittle cornea syndrome with a phenotype compatible with the extraskeletal features of OI but also with EDS.<\/jats:p>","DOI":"10.1007\/s00223-020-00721-3","type":"journal-article","created":{"date-parts":[[2020,7,15]],"date-time":"2020-07-15T14:03:50Z","timestamp":1594821830000},"page":"294-299","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Whole-Exome Sequencing Identifies Novel Compound Heterozygous ZNF469 Mutations in Two Siblings with Mild Brittle Cornea Syndrome"],"prefix":"10.1007","volume":"107","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1058-1307","authenticated-orcid":false,"given":"Tim","family":"Rolvien","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uwe","family":"Kornak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan J.","family":"Linke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Amling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Oheim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,7,15]]},"reference":[{"issue":"10028","key":"721_CR1","doi-asserted-by":"publisher","first-page":"1657","DOI":"10.1016\/S0140-6736(15)00728-X","volume":"387","author":"A Forlino","year":"2016","unstructured":"Forlino A, Marini JC (2016) Osteogenesis imperfecta. Lancet 387(10028):1657\u20131671","journal-title":"Lancet"},{"issue":"19","key":"721_CR2","doi-asserted-by":"publisher","first-page":"19259","DOI":"10.1074\/jbc.M414698200","volume":"280","author":"WA Cabral","year":"2005","unstructured":"Cabral WA, Makareeva E, Colige A, Letocha AD, Ty JM, Yeowell HN, Pals G, Leikin S, Marini JC (2005) Mutations near amino end of alpha1(I) collagen cause combined osteogenesis imperfecta\/Ehlers-Danlos syndrome by interference with N-propeptide processing. J Biol Chem 280(19):19259\u201319269","journal-title":"J Biol Chem"},{"issue":"1","key":"721_CR3","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1186\/1750-1172-8-78","volume":"8","author":"F Malfait","year":"2013","unstructured":"Malfait F, Symoens S, Goemans N, Gyftodimou Y, Holmberg E, Lopez-Gonzalez V, Mortier G, Nampoothiri S, Petersen MB, De Paepe A (2013) Helical mutations in type I collagen that affect the processing of the amino-propeptide result in an Osteogenesis Imperfecta\/Ehlers-Danlos Syndrome overlap syndrome. Orphanet J Rare Dis 8(1):78","journal-title":"Orphanet J Rare Dis"},{"key":"721_CR4","doi-asserted-by":"publisher","first-page":"17071","DOI":"10.1038\/cddiscovery.2017.71","volume":"3","author":"M Cassandri","year":"2017","unstructured":"Cassandri M, Smirnov A, Novelli F, Pitolli C, Agostini M, Malewicz M, Melino G, Raschella G (2017) Zinc-finger proteins in health and disease. Cell Death Discov 3:17071","journal-title":"Cell Death Discov"},{"issue":"5","key":"721_CR5","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1016\/j.ajhg.2008.04.001","volume":"82","author":"A Abu","year":"2008","unstructured":"Abu A, Frydman M, Marek D, Pras E, Nir U, Reznik-Wolf H, Pras E (2008) Deleterious mutations in the Zinc-Finger 469 gene cause brittle cornea syndrome. Am J Hum Genet 82(5):1217\u20131222","journal-title":"Am J Hum Genet"},{"issue":"1","key":"721_CR6","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1167\/iovs.09-4251","volume":"51","author":"AE Christensen","year":"2010","unstructured":"Christensen AE, Knappskog PM, Midtbo M, Gjesdal CG, Mengel-From J, Morling N, Rodahl E, Boman H (2010) Brittle cornea syndrome associated with a missense mutation in the zinc-finger 469 gene. Investig Ophthalmol Vis Sci 51(1):47\u201352","journal-title":"Investig Ophthalmol Vis Sci"},{"key":"721_CR7","doi-asserted-by":"publisher","first-page":"1511","DOI":"10.2147\/OPTH.S185287","volume":"13","author":"A Walkden","year":"2019","unstructured":"Walkden A, Burkitt-Wright E, Au L (2019) Brittle cornea syndrome: current perspectives. Clin Ophthalmol 13:1511\u20131516","journal-title":"Clin Ophthalmol"},{"issue":"6","key":"721_CR8","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1016\/j.ajhg.2011.05.007","volume":"88","author":"EMM Burkitt Wright","year":"2011","unstructured":"Burkitt Wright EMM, Spencer HL, Daly SB, Manson FDC, Zeef LAH, Urquhart J, Zoppi N, Bonshek R, Tosounidis I, Mohan M, Madden C, Dodds A, Chandler KE, Banka S, Au L, Clayton-Smith J, Khan N, Biesecker LG, Wilson M, Rohrbach M, Colombi M, Giunta C, Black GCM (2011) Mutations in PRDM5 in brittle cornea syndrome identify a pathway regulating extracellular matrix development and maintenance. Am J Hum Genet 88(6):767\u2013777","journal-title":"Am J Hum Genet"},{"issue":"19","key":"721_CR9","doi-asserted-by":"publisher","first-page":"2515","DOI":"10.1093\/bioinformatics\/bts462","volume":"28","author":"T Kamphans","year":"2012","unstructured":"Kamphans T, Krawitz PM (2012) GeneTalk: an expert exchange platform for assessing rare sequence variants in personal genomes. Bioinformatics 28(19):2515\u20132516","journal-title":"Bioinformatics"},{"issue":"W1","key":"721_CR10","doi-asserted-by":"publisher","first-page":"W114","DOI":"10.1093\/nar\/gkz330","volume":"47","author":"D Hombach","year":"2019","unstructured":"Hombach D, Schuelke M, Knierim E, Ehmke N, Schwarz JM, Fischer-Zirnsak B, Seelow D (2019) MutationDistiller: user-driven identification of pathogenic DNA variants. Nucleic Acids Res 47(W1):W114\u2013W120","journal-title":"Nucleic Acids Res"},{"issue":"8","key":"721_CR11","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1038\/nmeth0810-575","volume":"7","author":"JM Schwarz","year":"2010","unstructured":"Schwarz JM, Rodelsperger C, Schuelke M, Seelow D (2010) MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods 7(8):575\u2013576","journal-title":"Nat Methods"},{"issue":"5","key":"721_CR12","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1136\/ard.32.5.413","volume":"32","author":"P Beighton","year":"1973","unstructured":"Beighton P, Solomon L, Soskolne CL (1973) Articular mobility in an African population. Ann Rheum Dis 32(5):413\u2013418","journal-title":"Ann Rheum Dis"},{"issue":"11","key":"721_CR13","doi-asserted-by":"publisher","first-page":"1614","DOI":"10.1002\/humu.23645","volume":"39","author":"EA Rivera-Munoz","year":"2018","unstructured":"Rivera-Munoz EA, Milko LV, Harrison SM, Azzariti DR, Kurtz CL, Lee K, Mester JL, Weaver MA, Currey E, Craigen W, Eng C, Funke B, Hegde M, Hershberger RE, Mao R, Steiner RD, Vincent LM, Martin CL, Plon SE, Ramos E, Rehm HL, Watson M, Berg JS (2018) ClinGen Variant Curation Expert Panel experiences and standardized processes for disease and gene-level specification of the ACMG\/AMP guidelines for sequence variant interpretation. Hum Mutat 39(11):1614\u20131622","journal-title":"Hum Mutat"},{"issue":"11","key":"721_CR14","doi-asserted-by":"publisher","first-page":"2041","DOI":"10.1002\/jbmr.2873","volume":"31","author":"LA Burt","year":"2016","unstructured":"Burt LA, Liang Z, Sajobi TT, Hanley DA, Boyd SK (2016) Sex- and site-specific normative data curves for HR-pQCT. J Bone Miner Res 31(11):2041\u20132047","journal-title":"J Bone Miner Res"},{"key":"721_CR15","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1186\/1750-1172-8-68","volume":"8","author":"EM Burkitt Wright","year":"2013","unstructured":"Burkitt Wright EM, Porter LF, Spencer HL, Clayton-Smith J, Au L, Munier FL, Smithson S, Suri M, Rohrbach M, Manson FD, Black GC (2013) Brittle cornea syndrome: recognition, molecular diagnosis and management. Orphanet J Rare Dis 8:68","journal-title":"Orphanet J Rare Dis"},{"issue":"1","key":"721_CR16","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1002\/ajmg.c.31552","volume":"175","author":"F Malfait","year":"2017","unstructured":"Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, Bloom L, Bowen JM, Brady AF, Burrows NP, Castori M, Cohen H, Colombi M, Demirdas S, De Backer J, De Paepe A, Fournel-Gigleux S, Frank M, Ghali N, Giunta C, Grahame R, Hakim A, Jeunemaitre X, Johnson D, Juul-Kristensen B, Kapferer-Seebacher I, Kazkaz H, Kosho T, Lavallee ME, Levy H, Mendoza-Londono R, Pepin M, Pope FM, Reinstein E, Robert L, Rohrbach M, Sanders L, Sobey GJ, Van Damme T, Vandersteen A, van Mourik C, Voermans N, Wheeldon N, Zschocke J, Tinkle B (2017) The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C 175(1):8\u201326","journal-title":"Am J Med Genet C"},{"issue":"1","key":"721_CR17","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1002\/ajmg.a.37383","volume":"170","author":"AR Janecke","year":"2016","unstructured":"Janecke AR, Li B, Boehm M, Krabichler B, Rohrbach M, M\u00fcller T, Fuchs I, Golas G, Katagiri Y, Ziegler SG, Gahl WA (2016) The phenotype of the musculocontractural type of Ehlers-Danlos syndrome due to CHST14 mutations. Am J Med Genet A 170(1):103\u2013115","journal-title":"Am J Med Genet A"},{"issue":"9","key":"721_CR18","doi-asserted-by":"publisher","first-page":"1016","DOI":"10.1038\/ng.413","volume":"41","author":"B Reversade","year":"2009","unstructured":"Reversade B, Escande-Beillard N, Dimopoulou A, Fischer B, Chng SC, Li Y, Shboul M, Tham PY, Kayserili H, Al-Gazali L, Shahwan M, Brancati F, Lee H, O'Connor BD, Schmidt-von Kegler M, Merriman B, Nelson SF, Masri A, Alkazaleh F, Guerra D, Ferrari P, Nanda A, Rajab A, Markie D, Gray M, Nelson J, Grix A, Sommer A, Savarirayan R, Janecke AR, Steichen E, Sillence D, Hausser I, Budde B, Nurnberg G, Nurnberg P, Seemann P, Kunkel D, Zambruno G, Dallapiccola B, Schuelke M, Robertson S, Hamamy H, Wollnik B, Van Maldergem L, Mundlos S, Kornak U (2009) Mutations in PYCR1 cause cutis laxa with progeroid features. Nat Genet 41(9):1016\u20131021","journal-title":"Nat Genet"},{"issue":"6","key":"721_CR19","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1016\/S0002-9394(14)71125-0","volume":"123","author":"RC Wolfs","year":"1997","unstructured":"Wolfs RC, Klaver CC, Vingerling JR, Grobbee DE, Hofman A, de Jong PT (1997) Distribution of central corneal thickness and its association with intraocular pressure: The Rotterdam Study. Am J Ophthalmol 123(6):767\u2013772","journal-title":"Am J Ophthalmol"},{"issue":"3","key":"721_CR20","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1016\/j.ymgme.2013.04.014","volume":"109","author":"M Rohrbach","year":"2013","unstructured":"Rohrbach M, Spencer HL, Porter LF, Burkitt-Wright EMM, Burer C, Janecke A, Bakshi M, Sillence D, Al-Hussain H, Baumgartner M, Steinmann B, Black GCM, Manson FDC, Giunta C (2013) ZNF469 frequently mutated in the brittle cornea syndrome (BCS) is a single exon gene possibly regulating the expression of several extracellular matrix components. Mol Genet Metab 109(3):289\u2013295","journal-title":"Mol Genet Metab"},{"issue":"2","key":"721_CR21","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1016\/j.ajhg.2015.12.016","volume":"98","author":"G Divisato","year":"2016","unstructured":"Divisato G, Formicola D, Esposito T, Merlotti D, Pazzaglia L, Del Fattore A, Siris E, Orcel P, Brown JP, Nuti R, Strazzullo P, Benassi MS, Cancela ML, Michou L, Rendina D, Gennari L, Gianfrancesco F (2016) ZNF687 mutations in severe paget disease of bone associated with giant cell tumor. Am J Hum Genet 98(2):275\u2013286","journal-title":"Am J Hum Genet"},{"issue":"2","key":"721_CR22","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1007\/s00223-017-0269-0","volume":"101","author":"X Qi","year":"2017","unstructured":"Qi X, Pang Q, Wang J, Zhao Z, Wang O, Xu L, Mao J, Jiang Y, Li M, Xing X, Yu W, Asan XW (2017) Familial early-onset paget's disease of bone associated with a novel hnRNPA2B1 mutation. Calcif Tissue Int 101(2):159\u2013169","journal-title":"Calcif Tissue Int"}],"container-title":["Calcified Tissue International"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00223-020-00721-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00223-020-00721-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00223-020-00721-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,14]],"date-time":"2021-07-14T23:34:34Z","timestamp":1626305674000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00223-020-00721-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,15]]},"references-count":22,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2020,9]]}},"alternative-id":["721"],"URL":"https:\/\/doi.org\/10.1007\/s00223-020-00721-3","relation":{},"ISSN":["0171-967X","1432-0827"],"issn-type":[{"value":"0171-967X","type":"print"},{"value":"1432-0827","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,15]]},"assertion":[{"value":"30 April 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 June 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 July 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with Ethical Standards"}},{"value":"Tim Rolvien, Uwe Kornak, Stephan Linke, Michael Amling and Ralf Oheim declare that they have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"This case report is in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent was obtained from all individual patients included in the case report.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Research involving Human Participants & Informed Consent"}}]}}