{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T05:42:25Z","timestamp":1790401345903,"version":"4.1.0"},"reference-count":25,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2021,5,3]],"date-time":"2021-05-03T00:00:00Z","timestamp":1620000000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp; Gen Med"],"published-print":{"date-parts":[[2021,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Early\u2010onset osteoporosis (EOOP) is defined by low bone mineral density (BMD), which increases the risk of fracture. Although the prevalence of osteoporosis at a young age is unknown, low BMD is highly linked to genetic background. Heterozygous pathogenic variants in low\u2010density lipoprotein receptor\u2010related protein 5<jats:italic>(LRP5<\/jats:italic>) are associated with EOOP. This study aimed to investigate the genetic profile in patients with EOOP to better understand the variation in phenotype severity by using a targeted gene sequencing panel associated with bone fragility.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method and Results<\/jats:title><jats:p>We used a sequencing panel with 17 genes reported to be related to bone fragility for analysis of 68 patients with EOOP. We found a high positivity rate of EOOP with<jats:italic>LRP5<\/jats:italic>variants (14 patients, 20.6%). The remaining 79.4% of patients with EOOP but without<jats:italic>LRP5<\/jats:italic>variants showed variable disease severity, as observed in patients with at least one variant in this gene. One patient, with multiple fractures and spine L1\u2010L4 BMD<jats:italic>Z<\/jats:italic>\u2010score \u22122.9, carried a novel pathogenic homozygous variant, c.2918T&gt;C, p.(Leu973Pro), without any pseudoglioma. In addition to carrying the<jats:italic>LRP5<\/jats:italic>variant, 2 other patients carried a heterozygous variant in Wnt signaling pathway genes: dickkopf WNT signaling pathway inhibitor 1 (<jats:italic>DKK1<\/jats:italic>) [NM_012242.4: c.359G&gt;T, p.(Arg120Leu)] and Wnt family member 3A (<jats:italic>WNT3A<\/jats:italic>) [NM_033131.3: c.377G&gt;A, p. (Arg126His)]. As compared with single\u2010variant<jats:italic>LRP5<\/jats:italic>carriers, double\u2010variant carriers had a significantly lower BMD<jats:italic>Z<\/jats:italic>\u2010score (\u22124.1\u00a0\u00b1\u00a00.8) and higher mean number of fractures (6.0\u00a0\u00b1\u00a02.8 vs. 2.2\u00a0\u00b1\u00a01.9). Analysis of the family segregation suggests the inheritance of BMD trait.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Severe forms of EOOP may occur with carriage of 2 pathogenic variants in genes encoding regulators of the Wnt signaling pathway. Two\u2010variant carriers of Wnt pathway genes had severe EOOP. Moreover,<jats:italic>DKK1<\/jats:italic>and<jats:italic>WNT3A<\/jats:italic>genes should be included in next\u2010generation sequence analyses of bone fragility.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.1681","type":"journal-article","created":{"date-parts":[[2021,5,3]],"date-time":"2021-05-03T16:51:26Z","timestamp":1620060686000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["More severe phenotype of early\u2010onset osteoporosis associated with recessive form of<i>LRP5<\/i>and combination with<i>DKK1<\/i>or<i>WNT3A<\/i>"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9044-7348","authenticated-orcid":false,"given":"Caroline","family":"Caetano da Silva","sequence":"first","affiliation":[{"name":"Inserm U1132 and Universit\u00e9 de Paris Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manon","family":"Ricquebourg","sequence":"additional","affiliation":[{"name":"Inserm U1132 and Universit\u00e9 de Paris Paris France"},{"name":"Department of Rheumatology H\u00f4pital Lariboisi\u00e8re, AP\u2010HP Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Orcel","sequence":"additional","affiliation":[{"name":"Inserm U1132 and Universit\u00e9 de Paris Paris France"},{"name":"Department of Rheumatology H\u00f4pital Lariboisi\u00e8re, AP\u2010HP Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phanie","family":"Fabre","sequence":"additional","affiliation":[{"name":"Inserm U1132 and Universit\u00e9 de Paris Paris France"},{"name":"Department of Rheumatology H\u00f4pital Lariboisi\u00e8re, AP\u2010HP Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Funck\u2010Brentano","sequence":"additional","affiliation":[{"name":"Inserm U1132 and Universit\u00e9 de Paris Paris France"},{"name":"Department of Rheumatology H\u00f4pital Lariboisi\u00e8re, AP\u2010HP Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martine","family":"Cohen\u2010Solal","sequence":"additional","affiliation":[{"name":"Inserm U1132 and Universit\u00e9 de Paris Paris France"},{"name":"Department of Rheumatology H\u00f4pital Lariboisi\u00e8re, AP\u2010HP Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6990-863X","authenticated-orcid":false,"given":"Corinne","family":"Collet","sequence":"additional","affiliation":[{"name":"Inserm U1132 and Universit\u00e9 de Paris Paris France"},{"name":"Functional Unit of Molecular Biology H\u00f4pital Lariboisi\u00e8re, AP\u2010HP Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,5,3]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1086\/497706"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.20284"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-16-0990"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbm4.10020"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2388"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20061436"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2005.06.017"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00571-2"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1359\/JBMR.050101"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0080393"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00198-017-4150-9"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1097\/00006254-200108000-00023"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2350-13-26"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2012.06.011"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1215458"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp324"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-03-145169"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20880"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1516767"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1006\/geno.1996.0614"},{"key":"e_1_2_10_22_1","doi-asserted-by":"crossref","DOI":"10.1002\/jbmr.4197","article-title":"Clinical phenotype and relevance of LRP5 and LRP6 variants in patients with early\u2010onset osteoporosis (EOOP)","author":"St\u00fcrznickel J.","year":"2020","journal-title":"Journal of Bone and Mineral Research"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00198-012-2048-0"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1308223"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.299.11.1277"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12701"}],"container-title":["Molecular Genetics &amp; Genomic Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mgg3.1681","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/mgg3.1681","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mgg3.1681","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,30]],"date-time":"2024-08-30T03:05:38Z","timestamp":1724987138000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mgg3.1681"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,3]]},"references-count":25,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2021,6]]}},"alternative-id":["10.1002\/mgg3.1681"],"URL":"https:\/\/doi.org\/10.1002\/mgg3.1681","archive":["Portico"],"relation":{},"ISSN":["2324-9269","2324-9269"],"issn-type":[{"value":"2324-9269","type":"print"},{"value":"2324-9269","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,3]]},"assertion":[{"value":"2021-03-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-03-23","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-05-03","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e1681"}}