Genetic Diagnostics in Routine Osteological Assessment of Adult Low Bone Mass Disorders

pubmed: wnt1 2022-05-14

J Clin Endocrinol Metab. 2022 Mar 11:dgac147. doi: 10.1210/clinem/dgac147. Online ahead of print.


CONTEXT: Many different inherited and acquired conditions can result in premature bone fragility / low bone mass disorders (LBMD).

OBJECTIVE: We aimed at elucidating the impact of genetic testing on differential diagnosis of adult LBMD and at defining clinical criteria for predicting monogenic forms.

METHODS: Four clinical centers broadly recruited a cohort of 394 unrelated adult women before menopause and men younger than 55 years with a bone mineral density (BMD) Z-score <-2.0, and/or pathological fractures. After exclusion of secondary causes or unequivocal clinical/biochemical hallmarks of monogenic LBMD all participants were genotyped by targeted next-generation sequencing.

RESULTS: In total 20.8% of the participants carried rare disease-causing variants (DCV) in genes known to cause osteogenesis imperfecta (COL1A1, COL1A2), hypophosphatasia (ALPL), and early-onset osteoporosis (LRP5, PLS3, and WNT1). In addition, we identified rare DCV in ENPP1, LMNA, NOTCH2, and ZNF469. Three individuals had autosomal recessive, 75 autosomal dominant, and four X-linked disorders. 9.7% of the participants harbored variants of unknown significance. A regression analysis revealed that the likelihood of detecting a DCV correlated with a positive family history of osteoporosis, peripheral fractures (>2), and a high normal BMI. In contrast, mutation frequencies did not correlate with age, prevalent vertebral fractures, BMD, or biochemical parameters. In individuals without monogenic disease-causing rare variants, common variants predisposing for low BMD, e.g. in LRP5, were overrepresented.

CONCLUSION: The overlapping spectra of monogenic adult LBMD can be easily disentangled by genetic testing and the proposed clinical criteria can help to maximize the diagnostic yield.

PMID:35276006 | DOI:10.1210/clinem/dgac147