{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T12:26:57Z","timestamp":1768998417218,"version":"3.49.0"},"reference-count":28,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2020,4,14]],"date-time":"2020-04-14T00:00:00Z","timestamp":1586822400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100005632","name":"Narodowe Centrum Bada\u0144 i Rozwoju","doi-asserted-by":"publisher","award":["LIDER\/008\/431\/L\u20104\/12\/NCBR\/2013"],"award-info":[{"award-number":["LIDER\/008\/431\/L\u20104\/12\/NCBR\/2013"]}],"id":[{"id":"10.13039\/501100005632","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["UMO\u20102016\/22\/E\/NZ5\/00270"],"award-info":[{"award-number":["UMO\u20102016\/22\/E\/NZ5\/00270"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Birth Defects Research"],"published-print":{"date-parts":[[2020,5,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The <jats:italic>LRP4<\/jats:italic> gene encodes the highly conserved low\u2010density lipoprotein receptor\u2010related protein 4 (LRP4), which acts as a co\u2010receptor for sclerostin. Sclerostin and LRP4 negatively regulate WNT\/\u03b2\u2010catenin signaling pathway and lack of their inhibitory activity leads to constant osteoblastic differentiation. Consequently, increased bone formation occurs, which in the case of <jats:italic>LRP4<\/jats:italic> mutations results in sclerosteosis type 2 (SOST2). Alterations within the <jats:italic>LRP4<\/jats:italic> may also cause Cenani\u2010Lenz syndactyly syndrome (CLSS), congenital myasthenia or isolated syndactyly. Here, we have reported a patient, in whom we found a novel homozygous splice\u2010site variant c.1048+6T&gt;C in <jats:italic>LRP4<\/jats:italic> using whole exome sequencing. The patient was initially misdiagnosed with isolated CLSS\u2010like or Malik\u2010Percin\u2010like syndactyly. However, we have finally refined the diagnosis after comprehensive radiological examination and molecularly confirmed SOST2. Additionally, we have pointed here to the splicing variants as important causative alterations that may be overlooked in the molecular analysis due to the lack of advanced, reliable algorithms, built\u2010into the standard diagnostic pipelines. Using advanced in silico prediction tools of splice\u2010site alterations, including Alamut Visual software, we have demonstrated that the c.1048+6T&gt;C <jats:italic>LRP4<\/jats:italic> variant affects the native donor site and impairs an SC35 enhancer activity. Based on our experience, we recommend comprehensive radiological imaging, including X\u2010ray of the skull in each case of isolated syndactyly resulting from pathogenic variants of <jats:italic>LRP4<\/jats:italic>. We suggest that all previously reported patients carrying biallelic <jats:italic>LRP4<\/jats:italic> mutations, who were diagnosed with isolated syndactyly, could actually present with SOST2 that had been unrecognized due to the incomplete clinical and radiological assessment.<\/jats:p>","DOI":"10.1002\/bdr2.1676","type":"journal-article","created":{"date-parts":[[2020,4,14]],"date-time":"2020-04-14T15:04:22Z","timestamp":1586876662000},"page":"652-659","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["A novel biallelic splice\u2010site variant in the <scp><i>LRP4<\/i><\/scp> gene causes sclerosteosis 2"],"prefix":"10.1002","volume":"112","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0509-1696","authenticated-orcid":false,"given":"Ewelina","family":"Bukowska\u2010Olech","sequence":"first","affiliation":[{"name":"Department of Medical Genetics Poznan University of Medical Sciences  Poznan Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2493-898X","authenticated-orcid":false,"given":"Anna","family":"Sowi\u0144ska\u2010Seidler","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Poznan University of Medical Sciences  Poznan Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8803-646X","authenticated-orcid":false,"given":"Krzysztof","family":"Szcza\u0142uba","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Medical University of Warsaw  Warsaw Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4058-3901","authenticated-orcid":false,"given":"Aleksander","family":"Jamsheer","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Poznan University of Medical Sciences  Poznan Poland"},{"name":"Centers for Medical Genetics GENESIS  Poznan Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,4,14]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.150680"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1086\/318811"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.31.12.976"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00438491"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2016.10.007"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.2782"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12881-018-0646-1"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1159\/000051649"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty897"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.2884728"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.190330"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2010.03.004"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0912629107"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddt578"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/stem.541"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M504308200"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41431-018-0214-3"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2015.05.012"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/pd.5175"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23417"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1097\/00019605-200304000-00001"},{"key":"e_1_2_11_23_1","doi-asserted-by":"crossref","unstructured":"Tomita Y. Kim D. Magoori K. &Yamamoto T. T.(1998).A novel low\u2010density lipoprotein II membrane structure is abundant protein in heart1 with type 789 784\u2013789.","DOI":"10.1093\/oxfordjournals.jbchem.a022180"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1302\/0301-620X.40B2.208"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes10100732"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2016.10.010"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2018.07.022"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/cdg599"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1306555"}],"container-title":["Birth Defects Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fbdr2.1676","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bdr2.1676","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/bdr2.1676","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bdr2.1676","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,1]],"date-time":"2023-09-01T05:51:09Z","timestamp":1693547469000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/bdr2.1676"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,14]]},"references-count":28,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2020,5,15]]}},"alternative-id":["10.1002\/bdr2.1676"],"URL":"https:\/\/doi.org\/10.1002\/bdr2.1676","archive":["Portico"],"relation":{},"ISSN":["2472-1727","2472-1727"],"issn-type":[{"value":"2472-1727","type":"print"},{"value":"2472-1727","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,14]]},"assertion":[{"value":"2020-02-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-03-17","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-04-14","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}