Genetic aspects of the Paget's disease of bone: concerns on the introduction of DNA-based tests in the clinical practice. Advantages and disadvantages of its application.
BACKGROUND
A large amount of genetic studies have clearly demonstrated the existence of a genetic susceptibility to Paget's disease of bone (PDB). Although the disease is genetically heterogeneous, the SQSTM1/p62 gene, encoding a protein with a pathophysiological role in both osteoclast differentiation and activity, has been found worldwide to harbour germline mutations in most of the PDB patients from geographically distant populations originating from different areas of Europe, both in sporadic and familial cases.


METHODS
Thus, SQSTM1/p62 gene mutations may confer an increased lifetime risk of developing PDB.


RESULTS
Several different genotype-phenotype analyses have shown a high penetrance for such mutations. These results suggest the opportunity to perform genetic testing in affected individuals and then, after the identification of a SQSTM1/p62 gene germline mutation, in their relatives as a real and concrete strategy to increase the diagnostic sensitivity in most of the asymptomatic mutant carriers. However, it is of note to underlie that an incomplete penetrance for SQSTM1/p62 gene mutations has also been reported.


CONCLUSIONS
In light of all these contradictory evidences, a review on whether, when and why apply the DNA test to those subjects, its interpretation and clinical application is necessary. In fact, a growing number of preventive care options are now available to affected patients and families and the process of systematically assessing risk is becoming increasingly important for both patients and physicians.
Falchetti
Alberto
A
Regional Center for Hereditary Endocrine Tumors, Unit of Metabolic Bone Diseases, AOUC, Department of Internal Medicine, University of Florence, Florence, Italy.
Alberto
Falchetti
F
Marini
Francesca
F
Francesca
Marini
M
Masi
Laura
L
Laura
Masi
M
Amedei
Antonietta
A
Antonietta
Amedei
A
Brandi
Maria Luisa
ML
Luisa
Brandi Maria
BM
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D004247:DNA / Q000235:genetics*; D005820:Genetic Testing; D006801:Humans; D009154:Mutation / Q000235:genetics; D010001:Osteitis Deformans / Q000235:genetics*; D012307:Risk Factors; D000071456:Sequestosome-1 Protein
D048868:Adaptor Proteins, Signal Transducing; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D004247:DNA