Whole Genome Sequencing Unravels New Genetic Determinants of Early-Onset Familial Osteoporosis and Low BMD in Malta.

Chanelle Cilia,Donald Friggieri,Angela Xuereb-Anastasi,Melissa Marie Formosa,Josanne Vassallo

doi:10.3390/genes13020204

Chanelle Cilia, Donald Friggieri + Show 3 more

Open Access

https://doi.org/10.3390/genes13020204

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Journal: Genes	Publication Date: Jan 23, 2022
Citations: 2	License type: CC BY 4.0

Affiliation: University of Malta, Mater Dei Hospital

Abstract

Background: Osteoporosis is a skeletal disease with a strong genetic background. The study aimed to identify the genetic determinants of early-onset familial osteoporosis and low bone mineral density (BMD) in a two-generation Maltese family. Methods: Fifteen relatives aged between 28–74 years were recruited. Whole genome sequencing was conducted on 12 relatives and shortlisted variants were genotyped in the Malta Osteoporotic Fracture Study (MOFS) for replication. Results: Sequential variant filtering following a dominant inheritance pattern identified rare missense variants within SELP, TGF-β2 and ADAMTS20, all of which were predicted to be likely pathogenic and participate in osteoimmunology. TGF-β2 c.1136C>T was identified in five individuals from the MOFS in heterozygosity, four of whom had osteopenia/osteoporosis at the lumbar spine and hip, and/or had sustained a low-trauma fracture. Heterozygosity for the ADAMTS20 c.4090A>T was accompanied by lower total hip BMD (p = 0.018) and lower total serum calcium levels in MOFS (p < 0.01), recapitulating the findings from the family. Women carrying at least one copy of the alternative allele (TC/CC) for SELP c.2177T>C exhibited a tendency for lower lumbar spine BMD and/or wrist fracture history relative to women with TT genotype. Conclusions: Our findings suggest that the identified variants, alone or in combination, could be causal factors of familial osteoporosis and low BMD, requiring replication in larger collections.

Highlights

Osteoporosis is a complex, metabolic skeletal disease characterised by a reduction in bone mass and impaired bone microarchitecture resulting in increased bone fragility [1,2]
The underlying pathogenesis is influenced by a multitude of factors ranging from lifestyle factors, medication and co-existing diseases, and several genetic determinants identified through family- and population-based studies [7,8,9,10,11]
Stepwise variant filtering following an autosomal dominant inheritance pattern identified three conserved missense SNVs (Table 2) present in heterozygosity in the three affected osteoporotic male siblings (III1, III4 and III5), which were absent in the unaffected control (II10)

Summary

Introduction

Osteoporosis is a complex, metabolic skeletal disease characterised by a reduction in bone mass and impaired bone microarchitecture resulting in increased bone fragility [1,2].Bone mineral density (BMD) measurement by dual-energy X-ray absorptiometry (DXA)remains the accepted gold-standard for the non-invasive diagnosis of osteoporosis [3,4].Fractures are the major clinical consequence of osteoporosis, with those of the hip, vertebrae, humerus and wrist being the most common, debilitating and costly. Advancements in sequencing technologies accompanied by the availability of high-throughput sequencing have further enabled the identification of genetic factors that have, in turn, widened the knowledge on the complexity of bone biology and its governing factors. To date, these findings are only able to explain around 5% of the genetic variance [10], prompting the need for more studies. The study aimed to identify the genetic determinants of early-onset familial osteoporosis and low bone mineral density (BMD) in a two-generation Maltese family. Women carrying at least one copy of the alternative allele (TC/CC)

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