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INTRODUCTION: Osteoporosis is a complex metabolic and skeletal disease having a strong genetic background. Indeed, heritability of bone mineral density (BMD) in twin and family studies ranges from 50 to 85%. The aim of the study was to identify known and/or novel genes and gene variants that play a role in the susceptibility of primary osteoporosis in an extended Maltese family., MATERIALS AND METHODS: A 2-generation family having multiple relatives with osteoporosis (T-score, RESULTS: Eleven shortlisted variants segregating in a dominant inheritance pattern were identified in the affected relatives having a minor allele frequency of ≤2%. Variants included missense variants within ADAMTS20 (rs138035327), ARSD (rs78034736), BMP1 (rs368615556), CLDN18 (rs114998965), SELP (rs754086574), TGFβ2 (rs773943154), TRIM45 (rs146244405), PCDHGA11 (rs138408376), PLEC (rs138924815) and SPARC (rs41290587), and one stop gain variant within WDR89 (rs944955056)., CONCLUSIONS: Future studies will evaluate the shortlisted variants by replicating in the Malta Osteoporotic Fracture Study - a case-control collection of more than 1000 Maltese postmenopausal women and other extended Maltese pedigrees so as to determine association with osteoporosis and low-trauma fracture risk at different anatomical sites. Top candidates will in turn be assessed using functional studies., peer-reviewed

INTRODUCTION: Osteoporosis is a complex metabolic bone disease having a strong genetic background and high heritability rate. An extended Maltese family having multiple members affected with primary osteoporosis (T-score, METHODS: A 2-generation family consisting of 15 relatives with ages ranging from 28 to 74 years was recruited. Biochemical analysis excluded any comorbidities affecting bone health and none of the relatives had osteogenesis imperfecta. Whole genome sequencing was performed on 12 relatives and a number of filtering schemes together with in silico modelling were applied to narrow down the list of potentially causal variants., RESULTS: Five missense variants segregating in a dominant inheritance pattern were shortlisted, all of which had an alternative allele frequency of ≤1% in the 1000Genome project. The gene variants identified were ADAMTS20 rs138035327, BMP1 rs368615556, SELP rs754086574, TGF-b2 rs773943154 and TRIM45 rs146244405. Replication of the ADAMTS20 rs138035327 variant in a case-control collection of 1045 Maltese postmenopausal women was performed to determine association with bone mineral density, fragility fracture risk and biochemical parameters, including serum calcium and alkaline phosphatase. Heterozygosity was associated with a 2-fold increased risk of low serum calcium levels (odds ratio: 2.3 (95% confidence interval 1.1-5.0), p=0.03)., CONCLUSION: ADAMTS20 encodes a protease enzyme that cleaves aggrecan, required for cartilage and bone formation. Thus, functional follow-up is required to determine how the ADAMTS20 variant could be affecting calcium and bone homeostasis., DISCLOSURES: This work was funded by the Endeavour Scholarships Scheme., peer-reviewed