Gene Network of Susceptibility to Atypical Femoral Fractures Related to Bisphosphonate Treatment.

Natalia Garcia-Giralt,Raquel Rabionet,Nuria Martinez-Gil,Xavier Nogues,Neus Roca-Ayats,Diana Ovejero,Josep F Abril,Susanna Balcells,Santos Castañeda,Daniel Grinberg

doi:10.3390/genes13010146

Abstract

Atypical femoral fractures (AFF) are rare fragility fractures in the subtrocantheric or diaphysis femoral region associated with long-term bisphosphonate (BP) treatment. The etiology of AFF is still unclear even though a genetic basis is suggested. We performed whole exome sequencing (WES) analysis of 12 patients receiving BPs for at least 5 years who sustained AFFs and 4 controls, also long-term treated with BPs but without any fracture. After filtration and prioritization of rare variants predicted to be damaging and present in genes shared among at least two patients, a total of 272 variants in 132 genes were identified. Twelve of these genes were known to be involved in bone metabolism and/or AFF, highlighting DAAM2 and LRP5, both involved in the Wnt pathway, as the most representative. Afterwards, we intersected all mutated genes with a list of 34 genes obtained from a previous study of three sisters with BP-related AFF, identifying nine genes. One of these (MEX3D) harbored damaging variants in two AFF patients from the present study and one shared among the three sisters. Gene interaction analysis using the AFFNET web suggested a complex network among bone-related genes as well as with other mutated genes. BinGO biological function analysis highlighted cytoskeleton and cilium organization. In conclusion, several genes and their interactions could provide genetic susceptibility to AFF, that along with BPs treatment and in some cases with glucocorticoids may trigger this so feared complication.

Highlights

Atypical femoral fractures (AFF) are a very rare type of bone fractures associated mainly with bisphosphonates (BP) and very rarely with denosumab use [1,2,3]
In order to identify genes putatively involved in AFF, we first removed all variants identified in the four control samples, and selected those genes harboring rare genetic variants (ExAC and CSVS < 0.005) in at least two patients (Figure 1)
AFF have been reported to be related to several monogenic diseases like hypophosphatasia (HPP), X-linked hypophosphatemia, pycnodysostosis, osteopetrosis, osteoporosis pseudoglioma syndrome (OPPG), osteogenesis imperfecta (OI), and X-linked osteoporosis, in most cases, AFF does not occur in the setting of known monogenic causes

Summary

Introduction

Atypical femoral fractures (AFF) are a very rare type of bone fractures associated mainly with bisphosphonates (BP) and very rarely with denosumab use [1,2,3]. Many attempts have been made to identify these genetic factors that may predispose some BP users to sustain AFF. The authors proposed to perform GWAS with a larger sample size as well as whole-exome or whole-genome sequencing studies. This combination of studies would help to uncover the genetic background associated with BP-related AFF, which has a high genetic heterogeneity, sometimes associated with monogenic disorders [10,11] or otherwise with a polygenic etiology and large variability among individuals [12,13]

Methods

Results

Discussion

Conclusion