{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T07:16:28Z","timestamp":1778656588669,"version":"3.51.4"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2022,7,3]],"date-time":"2022-07-03T00:00:00Z","timestamp":1656806400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100002429","name":"Amgen","doi-asserted-by":"publisher","award":["20177230"],"award-info":[{"award-number":["20177230"]}],"id":[{"id":"10.13039\/100002429","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP1143364"],"award-info":[{"award-number":["APP1143364"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000272","name":"National Institute for Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014461","name":"NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust\/Institute of Cancer Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014461","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["asbmr.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["JBMR Plus"],"published-print":{"date-parts":[[2022,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Atypical femur fractures (AFFs) are rare complications of anti\u2010resorptive therapy. Devastating to the affected individual, they pose a public health concern because of reduced uptake of an effective treatment for osteoporosis due to patient concern. The risk of AFF is increased sixfold to sevenfold in patients of Asian ethnicity compared with Europeans. Genetic factors may underlie the AFF phenotype. Given the rarity of AFFs, studying familial AFF cases is valuable in providing insights into any genetic predisposition. We present two Singaporean families, one comprising a mother (1\u2010a) and a daughter (1\u2010b), and the other comprising two sisters (2\u2010a and 2\u2010b). All four cases presented with bisphosphonate\u2010associated AFF. Whole\u2010exome sequencing (WES) was performed on 1\u2010b, 2\u2010a, and 2\u2010b. DNA for 1\u2010a was not available. Variants were examined using a candidate gene approach comprising a list of genes previously associated with AFF in the literature, as well as using unbiased filtering based on dominant and\/or recessive inheritance patterns. Using a candidate gene approach, rare variants shared between all three cases were not identified. A rare variant in\n                    <jats:italic>TMEM25<\/jats:italic>\n                    , shared by the two sisters (2\u2010a and 2\u2010b), was identified. A rare heterozygous\n                    <jats:italic>PLOD2<\/jats:italic>\n                    variant was present in the daughter case with AFF (1\u2010b), but not in the sisters. A list of potential genetic variants for AFF was identified after variant filtering and annotation analysis of the two sisters (2\u2010a and 2\u2010b), including a Gly35Arg variant in\n                    <jats:italic>TRAF4<\/jats:italic>\n                    , a gene required for normal skeletal development. Although the findings from this genetic analysis are inconclusive, a familial aggregation of AFFs is suggestive of a genetic component in AFF pathogenesis. We provide a comprehensive list of rare variants identified in these AFF familial cases to aid future genetic studies. \u00a9 2022 The Authors.\n                    <jats:italic>JBMR Plus<\/jats:italic>\n                    published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.\n                  <\/jats:p>","DOI":"10.1002\/jbm4.10659","type":"journal-article","created":{"date-parts":[[2022,6,11]],"date-time":"2022-06-11T06:24:16Z","timestamp":1654928656000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Whole Exome Sequencing in Two\n                    <scp>Southeast<\/scp>\n                    Asian Families With Atypical Femur Fractures"],"prefix":"10.1093","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6748-6303","authenticated-orcid":false,"given":"Wei","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Internal Medicine Erasmus Medical Center  Rotterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8846-6168","authenticated-orcid":false,"given":"Hanh H.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Medicine School of Clinical Sciences, Monash University  Clayton VI Australia"},{"name":"Department of Endocrinology Monash Health  Clayton VI Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7701-6663","authenticated-orcid":false,"given":"Denise M.","family":"van de Laarschot","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Erasmus Medical Center  Rotterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tet Sen","family":"Howe","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Singapore General Hospital  Singapore Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joyce S.B.","family":"Koh","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Singapore General Hospital  Singapore Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frances","family":"Milat","sequence":"additional","affiliation":[{"name":"Department of Medicine School of Clinical Sciences, Monash University  Clayton VI Australia"},{"name":"Department of Endocrinology Monash Health  Clayton VI Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeroen G.J.","family":"van Rooij","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Erasmus Medical Center  Rotterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joost A.M.","family":"Verlouw","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Erasmus Medical Center  Rotterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bram C.J.","family":"van der Eerden","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Erasmus Medical Center  Rotterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Stevenson","sequence":"additional","affiliation":[{"name":"Academic Endocrine Unit, Radcliffe Department of Medicine University of Oxford  Oxford UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1438-3220","authenticated-orcid":false,"given":"Rajesh V.","family":"Thakker","sequence":"additional","affiliation":[{"name":"Academic Endocrine Unit, Radcliffe Department of Medicine University of Oxford  Oxford UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. Carola","family":"Zillikens","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Erasmus Medical Center  Rotterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter R.","family":"Ebeling","sequence":"additional","affiliation":[{"name":"Department of Medicine School of Clinical Sciences, Monash University  Clayton VI Australia"},{"name":"Department of Endocrinology Monash Health  Clayton VI Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2022,7,3]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.1998"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005373-199707000-00027"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00198-019-05112-5"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1210\/er.2018-00001"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinbiomech.2014.08.001"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.3109\/17453674.2015.1004149"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2010.05.019"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.1719"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2012.02.632"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2016.01.002"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1916525"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2020.115319"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.2547"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbm4.10024"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11914-021-00658-y"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1612804"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.3580"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1359\/JBMR.041110"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1080\/09513590.2017.1301921"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbm4.10064"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbspin.2016.11.014"},{"issue":"1","key":"e_1_2_11_23_1","first-page":"s295","article-title":"TNSALP mutation analysis in women with atypical femoral fracture and bisphosphonate therapy for osteoporosis","volume":"28","author":"Sum M","year":"2013","journal-title":"J Bone Miner Res"},{"key":"e_1_2_11_24_1","unstructured":"LauS McInerney\u2010LeoA Lanoda\u2010BassongaE.Homozygous variant in cathepsin K in a family with multiple cases of bilateral atypical femoral fracture but without clinical features of pyknodysostosis abstract# 87. Combined 2017 Meeting of the Australian and New Zealand Bone and Mineral Society (ANZBMS) and the International Federation of Musculoskeletal Research Societies (IFMRS) in Conjunction With the Japanese Society for Bone and Mineral Research (JSBMR)2017. p.17\u201021."},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgac022"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aav9166"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes13010146"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1016"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03819-2"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab1061"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddiscovery.2017.71"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.3348"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00223-013-9723-9"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar4013"},{"issue":"2","key":"e_1_2_11_35_1","first-page":"429","article-title":"Identification and characterization of human TMEM25 and mouse Tmem25 genes in silico","volume":"12","author":"Katoh M","year":"2004","journal-title":"Oncol Rep"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2018.01345"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI122599"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22147395"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/dey264"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.052124799"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-019-0328-3"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12192-018-0953-7"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12551-010-0040-5"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2021.650667"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1002\/cne.23242"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11914-013-0145-4"}],"container-title":["JBMR Plus"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jbm4.10659","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jbm4.10659","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jbm4.10659","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,14]],"date-time":"2024-03-14T09:57:20Z","timestamp":1710410240000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmrplus\/article\/7478957"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,3]]},"references-count":45,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2022,8]]}},"alternative-id":["10.1002\/jbm4.10659"],"URL":"https:\/\/doi.org\/10.1002\/jbm4.10659","archive":["Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.1002\/JBM4.10659\/v2\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/JBM4.10659\/v1\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/JBM4.10659\/v2\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/JBM4.10659\/v1\/review2","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/JBM4.10659\/v2\/review2","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/JBM4.10659\/v1\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/JBM4.10659\/v2\/review1","asserted-by":"object"}]},"ISSN":["2473-4039","2473-4039"],"issn-type":[{"value":"2473-4039","type":"print"},{"value":"2473-4039","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,3]]},"assertion":[{"value":"2022-02-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-06-06","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-07-03","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e10659"}}