Primary Osteoporosis in Young Adults: Genetic Basis and Identification of Novel Variants in Causal Genes

Abstract

Genetic 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 <i>Z</i>-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 (<i>Z</i>-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 <i>COL1A2</i> (<i>n</i> = 4), <i>PLS3</i> (<i>n</i> = 2), <i>WNT1</i> (<i>n</i> = 4), or <i>DKK1</i> (<i>n</i> = 1). We showed a high prevalence of pathogenic variants in <i>LRP5</i>: 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 <i>LRP5</i> 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. <i>JBMR Plus</i> is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.