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

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 and , all of which were predicted to be likely pathogenic and participate in osteoimmunology. 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 c.4090A>T was accompanied by lower total hip BMD ( 0.018) and lower total serum calcium levels in MOFS ( < 0.01), recapitulating the findings from the family. Women carrying at least one copy of the alternative allele (TC/CC) for 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.