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 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.

Osteoporosis in Premenopausal Women: A Clinical Narrative Review by the ECTS and the IOF

“…Novel variants were found in 11 subjects (regarding the following genes: COL1A2, WNT1, PLS3, and DKK1); however, there was no control group. In addition, previously reported osteoporosis-causing variants in the LRP5 gene were found in 22 patients (89). In contrast, 45.5% of the patients studied carried no genetic variants in the examined genes.…”

Pregnancy and lactation, a challenge for the skeleton

“…Screening for an underlying monogenetic bone disorder has been further proposed in patients in whom PLO occurs together with one of the following features: joint hypermobility and blue sclerae (indicative of osteogenesis imperfecta), congenital blindness, or severely reduced vision (as associated with osteoporosis pseudoglioma syndrome). Nowadays, genetic diagnostics are often offered in multi-gene test panels labeled 'osteogenesis imperfecta and related conditions' which may include additional variants derived from familial osteoporosis, osteogenesis imperfecta, and genome-wide association studies, studies (80,81,82). The indication for genetic testing should be seriously considered, because a diagnosis has significant implications for the patient as well as their relatives.…”

Clinical Phenotype and Relevance of LRP5 and LRP6 Variants in Patients With Early-Onset Osteoporosis (EOOP)

“…(22) This is most likely explained by the proposed role of LRP6 as a coreceptor for PTH signaling. (23)(24)(25) Although various studies analyzing the effects of mutations in both Lrp5 and Lrp6 have been performed in mice, human studies addressing this issue are limited (26) but potentially of diagnostic and therapeutic relevance. Here, we present EOOP patients and family members carrying genetic variants in LRP5 or LRP6 with varying degrees of pathogenicity.…”