Abstract
ABSTRACTGenetic determinants contribute to osteoporosis and enhance the risk of fracture. Genomewide association studies of unselected population‐based individuals or families have identified polymorphisms in several genes related to low bone density, but not in osteoporotic patients with Z‐score < −2.0 SD with fragility fracture(s). The aim of this study was to determine the causal genes of idiopathic osteoporosis in the adulthood. Also, we used next‐generation sequencing of candidate genes in a cohort of 123 young or middle‐aged adults with idiopathic osteoporosis. All patients were included if they had a low bone mineral density (Z‐score < −2 SD), a diagnosis before age 55 years (mean ± SD, 48.4 ± 10.6 years; mean ± SD age at first fracture, 30.4 ± 17.4 years) and fracture or not. We found that 11 patients carried rare or novel variants in COL1A2 (n = 4), PLS3 (n = 2), WNT1 (n = 4), or DKK1 (n = 1). We showed a high prevalence of pathogenic variants in LRP5: 22 patients (17.8%) had the p.Val667Met variant, including three at the homozygous level and 16 (13%) carrying a novel or very rare variant. Functional analysis revealed that the LRP5 missense variants resulted in reduced luciferase activity, which indicates reduced activation of canonical WNT signaling. The clinical phenotype of patients carrying causal gene variants was indistinguishable. In conclusion, molecular screening of young osteoporotic adults revealed several variants and could be useful to characterize susceptibility genes for personalizing treatment, in particular for the new anabolic drugs.© 2017 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.
Highlights
Osteoporosis is defined as a skeletal disorder of reduced bone strength leading to increased risk of fracture
The heritability of bone mineral density (BMD) is estimated at 60% to 80% in families and twins.[4,5] the heritability of osteoporotic fractures, the final clinical outcome of low BMD, has moderate heritability, 50% to 70%.(6,7) Genomewide association studies of unselected population-based individuals have revealed several genes associated with low bone mass and risk of fracture.[8]. Other rare mutations have been reported in young adults with osteoporosis, in extracellular matrix genes or cell factors that regulate bone remodeling
next-generation sequencing (NGS) sequencing revealed mutations in genes described in several rare diseases associated with bone fragility in 11 patients: COL1A2 (n 1⁄4 4), plastin 3 (PLS3) (n 1⁄4 2), Wnt family member 1 (WNT1) (n 1⁄4 4), and DKK1 (n 1⁄4 1) (Fig. 1)
Summary
Osteoporosis is defined as a skeletal disorder of reduced bone strength leading to increased risk of fracture. Called idiopathic, in young and middle-aged patients is rare, and the prevalence is poorly described. The heritability of BMD is estimated at 60% to 80% in families and twins.[4,5] the heritability of osteoporotic fractures, the final clinical outcome of low BMD, has moderate heritability, 50% to 70%.(6,7) Genomewide association studies of unselected population-based individuals have revealed several genes associated with low bone mass and risk of fracture.[8] Other rare mutations have been reported in young adults with osteoporosis, in extracellular matrix genes or cell factors that regulate bone remodeling. Heterozygous Wnt family member 1 (WNT1) mutations have been found in adults with dominant early-onset osteoporosis and a homozygous mutation causes severe osteogenesis imperfecta.[9] Mutations in plastin 3 (PLS3),(10) a gene encoding plastin 3, which is involved in actin bundle
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