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Article

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

1
Department of Applied Biomedical Science, Faculty of Health Sciences, University of Malta, MSD 2080 Msida, Malta
2
Centre for Molecular Medicine and Biobanking, University of Malta, MSD 2080 Msida, Malta
3
Department of Medicine, Faculty of Medicine and Surgery, University of Malta, MSD 2080 Msida, Malta
4
Division of Endocrinology, Mater Dei Hospital, MSD 2090 Msida, Malta
*
Author to whom correspondence should be addressed.
Academic Editors: Susanna Balcells, Daniel Grinberg and Natalia Garcia-Giralt
Genes 2022, 13(2), 204; https://doi.org/10.3390/genes13020204
Received: 10 December 2021 / Revised: 17 January 2022 / Accepted: 18 January 2022 / Published: 23 January 2022
(This article belongs to the Special Issue Genetic Disorders of Bone)
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. View Full-Text
Keywords: familial osteoporosis; BMD; whole genome sequencing; SELP; TGF-β2; ADAMTS20 familial osteoporosis; BMD; whole genome sequencing; SELP; TGF-β2; ADAMTS20
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MDPI and ACS Style

Cilia, C.; Friggieri, D.; Vassallo, J.; Xuereb-Anastasi, A.; Formosa, M.M. Whole Genome Sequencing Unravels New Genetic Determinants of Early-Onset Familial Osteoporosis and Low BMD in Malta. Genes 2022, 13, 204. https://doi.org/10.3390/genes13020204

AMA Style

Cilia C, Friggieri D, Vassallo J, Xuereb-Anastasi A, Formosa MM. Whole Genome Sequencing Unravels New Genetic Determinants of Early-Onset Familial Osteoporosis and Low BMD in Malta. Genes. 2022; 13(2):204. https://doi.org/10.3390/genes13020204

Chicago/Turabian Style

Cilia, Chanelle, Donald Friggieri, Josanne Vassallo, Angela Xuereb-Anastasi, and Melissa M. Formosa. 2022. "Whole Genome Sequencing Unravels New Genetic Determinants of Early-Onset Familial Osteoporosis and Low BMD in Malta" Genes 13, no. 2: 204. https://doi.org/10.3390/genes13020204

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