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Although the pathogenesis of AFFs is unknown, their identification in bisphosphonate\u2010na\u00efve individuals and in monogenetic bone disorders has led to the hypothesis that genetic factors predispose to AFF. Our aim was to review and summarize the evidence for genetic factors in individuals with AFF. We conducted structured literature searches and hand\u2010searching of conference abstracts\/reference lists for key words relating to AFF and identified 2566 citations. Two individuals independently reviewed citations for (i) cases of AFF in monogenetic bone diseases and (ii) genetic studies in individuals with AFF. AFFs were reported in 23 individuals with the following 7 monogenetic bone disorders (<jats:italic>gene<\/jats:italic>): osteogenesis imperfecta (<jats:italic>COL1A1\/COL1A2<\/jats:italic>), pycnodysostosis (<jats:italic>CTSK<\/jats:italic>), hypophosphatasia (<jats:italic>ALPL<\/jats:italic>), X\u2010linked osteoporosis (<jats:italic>PLS3<\/jats:italic>), osteopetrosis, X\u2010linked hypophosphatemia (<jats:italic>PHEX<\/jats:italic>), and osteoporosis pseudoglioma syndrome (<jats:italic>LRP5<\/jats:italic>). In 8 cases (35%), the monogenetic bone disorder was uncovered after the AFF occurred. Cases of bisphosphonate\u2010na\u00efve AFF were reported in pycnodysostosis, hypophosphatasia, osteopetrosis, X\u2010linked hypophosphatemia, and osteoporosis pseudoglioma syndrome. A pilot study in 13 AFF patients and 268 controls identified a greater number of rare variants in AFF cases using exon array analysis. A whole\u2010exome sequencing study in 3 sisters with AFFs showed, among 37 shared genetic variants, a p.Asp188Tyr mutation in the <jats:italic>GGPS1<\/jats:italic> gene in the mevalonate pathway, critical to osteoclast function, which is also inhibited by bisphosphonates. Two studies completed targeted <jats:italic>ALPL<\/jats:italic> gene sequencing, an <jats:italic>ALPL<\/jats:italic> heterozygous mutation was found in 1 case of a cohort of 11 AFFs, whereas the second study comprising 10 AFF cases did not find mutations in <jats:italic>ALPL<\/jats:italic>. Targeted sequencing of <jats:italic>ALPL<\/jats:italic>, <jats:italic>COL1A1<\/jats:italic>, <jats:italic>COL1A2<\/jats:italic>, and <jats:italic>SOX9<\/jats:italic> genes in 5 cases of AFF identified a variant in COL1A2 in 1 case. These findings suggest a genetic susceptibility for AFFs. A large multicenter collaborative study of well\u2010phenotyped AFF cases and controls is needed to understand the role of genetics in this uncommon condition. \u00a9 2017 The Authors <jats:italic>JBMR Plus<\/jats:italic> published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jbm4.10024","type":"journal-article","created":{"date-parts":[[2017,11,14]],"date-time":"2017-11-14T13:18:42Z","timestamp":1510665522000},"page":"1-11","source":"Crossref","is-referenced-by-count":76,"title":["Genetic Risk Factors for Atypical Femoral Fractures (AFFs): A Systematic Review"],"prefix":"10.1093","volume":"2","author":[{"given":"Hanh H","family":"Nguyen","sequence":"first","affiliation":[{"name":"Department of Medicine School of Clinical Sciences Monash University Clayton Australia"},{"name":"Department of Endocrinology Monash Health Clayton Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise M","family":"van de Laarschot","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Erasmus Medical Centre Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annemieke JMH","family":"Verkerk","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Erasmus Medical Centre Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frances","family":"Milat","sequence":"additional","affiliation":[{"name":"Department of Medicine School of Clinical Sciences Monash University Clayton Australia"},{"name":"Department of Endocrinology Monash Health Clayton Australia"},{"name":"Hudson Institute of Medical Research Clayton Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M Carola","family":"Zillikens","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Erasmus Medical Centre Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter R","family":"Ebeling","sequence":"additional","affiliation":[{"name":"Department of Medicine School of Clinical Sciences Monash University Clayton Australia"},{"name":"Department of Endocrinology Monash Health Clayton Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2018,1,3]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.2888"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.253"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.1998"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2004-0952"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.2832"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.2565"},{"issue":"9319","key":"e_1_2_7_8_1","first-page":"1761","article-title":"Epidemiology and outcomes of osteoporotic fractures. 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