Whole-exome sequencing implicates a variant in lysyl oxidase like 4 in the pathogenesis of familial atypical femur fractures.

Abstract

Atypical femur fractures (AFFs) are rare adverse events associated with the use of bisphosphonates but the pathophysiology is unclear. They have been reported to cluster in families and have occurred in patients with monogenetic bone diseases even without bisphosphonate use, suggesting an underlying genetic susceptibility. The aim of this study was to identify a genetic cause for AFF in a Caucasian family with three siblings with bisphosphonate- associated AFFs among seven family members with osteoporosis. By whole-exome sequencing, we identified a rare missence variant c.G1063A (p.Gly355Ser) in lysyl oxidase like 4 (LOXL4) among 64 heterozygous rare, protein-altering variants shared by the three siblings with AFFs. This variant was also found in a fourth sibling with a low-trauma femur fracture above the knee, not fulfilling all the ASBMR criteria of AFF but it was not present in the other family members with osteoporosis but without an AFF. The same variant in LOXL4 was also found in one of 73 unrelated European AFF patients. LOXL4 is involved in collagen and elastin cross-linking and likely relevant for bone repair mechanisms. Skin fibroblast-derived osteoblasts from the unrelated patient with the LOXL4 variant expressed less collagen type I and elastin, while osteogenic differentiation and mineralization were enhanced compared with controls. We hypothesize that this LOXL4 variant may affect collagen deposition in bone and healing of microcracks, eventually leading to AFFs. In summary, family-based whole-exome sequencing implicates a variant in LOXL4 in AFFs but not in osteoporosis. The findings need further replication in larger AFF cohorts and more functional evaluations.