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

Cilia, Chanelle; Friggieri, Donald; Vassallo, Josanne; Xuereb-Anastasi, Angela; Formosa, Melissa M.

doi:10.3390/genes13020204

Cited by 3 publications

(2 citation statements)

References 105 publications

(113 reference statements)

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“…Sturnickel et al [5] found 25 individuals with LRP5 allelic variants and 6 with LRP6 variants among 371 patients with early-onset osteoporosis, but none of the LRP6 variants were classified as damaging. However, no LRP6 mutations were found in other studies of osteoporosis in young people or among some familiar cases of osteoporosis [11][12][13][14]. Interestingly, recent reports show that, similarly to gain-of-function mutations of LRP5, some LRP6 activating mutations may result in generalized high bone mass or localized bone sclerosis [15,16].…”

Section: Discussionmentioning

confidence: 98%

An LRP6 mutation (Arg360His) associated with low bone mineral density but not cardiovascular events in a Caucasian family

et al. 2022

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We present a family with a rare mutation of the LRP6 gene and for the first time provide evidence for its association with low bone mineral density. Introduction The Wnt pathway plays a critical role in bone homeostasis. Pathogenic variants of the Wnt co-receptor LRP6 have been associated with abnormal skeletal phenotypes or increased risk of cardiovascular events. Patient and methods Here we report an index premenopausal patient and her family carrying a rare missense LRP6 pathogenic variant (rs141212743; 0.0002 frequency among Europeans). This variant has been previously associated with metabolic syndrome and atherosclerosis, in the presence of normal bone mineral density. However, the LRP6 variant was associated with low bone mineral density in this family, without evidence for association with serum lipid levels or cardiovascular events. Conclusion Thus, this novel association shows that LRP6 pathogenic variants may be involved in some cases of early-onset osteoporosis, but the predominant effect, either skeletal or cardiovascular, may vary depending on the genetic background or other acquired factors.

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Section: Discussionmentioning

confidence: 98%

An LRP6 mutation (Arg360His) associated with low bone mineral density but not cardiovascular events in a Caucasian family

et al. 2022

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“…Genetic susceptibility to osteoporosis has been extensively studied [ 1 , 2 , 4 ]. One of the most important risk factors for the development of OP is a positive family history underlying the importance of genetic factors in the development of disease [ 1 , 5 – 8 ]. In addition to genetic factors, old age, female sex, and low mineral density are the strongest determinants of osteoporosis [ 9 , 10 ].…”

Section: Osteoporosis and Genetic Variationsmentioning

confidence: 99%

Copy Number Variation and Osteoporosis

Lovšin

2023

Curr Osteoporos Rep

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Purpose of Review The purpose of this review is to summarize recent findings on copy number variations and susceptibility to osteoporosis. Recent Findings Osteoporosis is highly influenced by genetic factors, including copy number variations (CNVs). The development and accessibility of whole genome sequencing methods has accelerated the study of CNVs and osteoporosis. Recent findings include mutations in novel genes and validation of previously known pathogenic CNVs in monogenic skeletal diseases. Identification of CNVs in genes previously associated with osteoporosis (e.g. RUNX2, COL1A2, and PLS3) has confirmed their importance in bone remodelling. This process has been associated also with the ETV1-DGKB, AGBL2, ATM, and GPR68 genes, identified by comparative genomic hybridisation microarray studies. Importantly, studies in patients with bone pathologies have associated bone disease with the long non-coding RNA LINC01260 and enhancer sequences residing in the HDAC9 gene. Summary Further functional investigation of genetic loci harbouring CNVs associated with skeletal phenotypes will reveal their role as molecular drivers of osteoporosis.

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Exploring DNA methylation profiles in the pathogenesis of human osteoporosis via whole-genome bisulfite sequencing

Zhang,

Zhong,

et al. 2024

Preprint

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Background Osteoporosis is a prevalent bone metabolic disorder characterized by reduced bone mass, disruption of bone microarchitecture, and increased bone fragility, leading to a heightened risk of fracture. This condition significantly impairs patients' quality of life and increases mortality risk. Emerging evidence suggests that DNA methylation may play a crucial role in regulating the expression of genes related to bone metabolism, thereby influencing the development of osteoporosis. However, the precise relationship between DNA methylation and osteoporosis remains unclear and warrants further investigation. Results Our study revealed significant differences in both the quantity and ratio of DNA methylation between individuals with osteoporosis and healthy controls, with differences predominantly occurring in CpG islands. GO/KEGG enrichment analyses highlighted distinct osteoporosis-related gene pathways. Notably, we identified two genes, TF and TGFB1, located on chromosomes 3 and 19, respectively, that are potentially involved in the pathogenesis of osteoporosis and are broadly involved in various diseases and biological processes. Conclusions These findings indicate distinct methylation patterns between osteoporosis patients and healthy individuals, with differential methylation levels in genes associated with osteoporosis. This research offers new insights into the epigenetic mechanisms underlying osteoporosis.

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

Cited by 3 publications

References 105 publications

An LRP6 mutation (Arg360His) associated with low bone mineral density but not cardiovascular events in a Caucasian family

An LRP6 mutation (Arg360His) associated with low bone mineral density but not cardiovascular events in a Caucasian family

Copy Number Variation and Osteoporosis

Exploring DNA methylation profiles in the pathogenesis of human osteoporosis via whole-genome bisulfite sequencing

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