Whole Exome Sequencing in Two Southeast Asian Families With Atypical Femur Fractures

Wei Zhou, Hanh H. Nguyen, Denise M. van de Laarschot, Tet Sen Howe, Joyce S.B. Koh, Frances Milat, Jeroen G.J. van Rooij, Joost A.M. Verlouw, Bram C.J. van der Eerden, Mark Stevenson, Rajesh V. Thakker, M. Carola Zillikens, Peter R. Ebeling*

*Corresponding author for this work

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Abstract

Atypical femur fractures (AFFs) are rare complications of anti-resorptive 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-a) and a daughter (1-b), and the other comprising two sisters (2-a and 2-b). All four cases presented with bisphosphonate-associated AFF. Whole-exome sequencing (WES) was performed on 1-b, 2-a, and 2-b. DNA for 1-a 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 TMEM25, shared by the two sisters (2-a and 2-b), was identified. A rare heterozygous PLOD2 variant was present in the daughter case with AFF (1-b), 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-a and 2-b), including a Gly35Arg variant in TRAF4, 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.

Original languageEnglish
Article numbere10659
JournalJBMR Plus
Volume6
Issue number8
DOIs
Publication statusPublished - Aug 2022

Bibliographical note

Funding Information:
Jaap Schouten Foundation, Rotterdam, The Netherlands, kindly provided funding for analyzing the genetic background of atypical femur fractures. PRE and MCZ received research funding from the National Health & Medical Research Council of Australia (grant number APP1143364), and PRE received a grant from Amgen (grant number 20177230). RVT received funding from the Oxford Biomedical Research Centre Program of the National Institute for Health Research (NIHR, UK). The funding agencies played no role in the study design or in data collection and analyses. We thank the carers of, and patients from, these families with AFF for participating in this study. We are grateful to Annemieke J.M.H. Verkerk for her advice on the analyses and display of results and Marijke Koedam for facilitating and assistance with PCR and Sanger Sequencing. We appreciate the support from the Jaap Schouten Foundation, NHMRC, Amgen and the Oxford Biomedical Research Centre Program of the National Institute for Health Research (NIHR) for research funding. Authors' roles: Study design: PRE and MCZ. Study conduct: HHN and WZ. Data collection: HTS, JK, FM, PRE, HHN, and MCZ. Data analysis: HHN, WZ, and MS. Supervision: PRE, MCZ, JVR, and RVT. Data interpretation: HHN, WZ, MCZ, PRE, JVR, MS, and RVT. Drafting manuscript: HHN and WZ. Critically revising manuscript content: all co-authors. Approving final version of manuscript: all co-authors.

Funding Information:
Jaap Schouten Foundation, Rotterdam, The Netherlands, kindly provided funding for analyzing the genetic background of atypical femur fractures. PRE and MCZ received research funding from the National Health & Medical Research Council of Australia (grant number APP1143364), and PRE received a grant from Amgen (grant number 20177230). RVT received funding from the Oxford Biomedical Research Centre Program of the National Institute for Health Research (NIHR, UK). The funding agencies played no role in the study design or in data collection and analyses. We thank the carers of, and patients from, these families with AFF for participating in this study. We are grateful to Annemieke J.M.H. Verkerk for her advice on the analyses and display of results and Marijke Koedam for facilitating and assistance with PCR and Sanger Sequencing. We appreciate the support from the Jaap Schouten Foundation, NHMRC, Amgen and the Oxford Biomedical Research Centre Program of the National Institute for Health Research (NIHR) for research funding.

Publisher Copyright:
© 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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