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

J Clin Endocrinol Metab. 2022 Jun 16;107(7):e3048-e3057. doi: 10.1210/clinem/dgac147.

Abstract

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

Objective: We aimed to elucidate the impact of genetic testing on differential diagnosis of adult LBMDs 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 LBMDs, all participants were genotyped by targeted next-generation sequencing.

Results: In total, 20.8% of the participants carried rare disease-causing variants (DCVs) in genes known to cause osteogenesis imperfecta (COL1A1, COL1A2), hypophosphatasia (ALPL), and early-onset osteoporosis (LRP5, PLS3, and WNT1). In addition, we identified rare DCVs in ENPP1, LMNA, NOTCH2, and ZNF469. Three individuals had autosomal recessive, 75 autosomal dominant, and 4 X-linked disorders. A total of 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 body mass index (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 (eg, 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.

Keywords: genetic risk score; genotype-phenotype correlation; low bone mass disorder; monogenic disorder; osteoporosis; rare genetic variant.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Bone Density / genetics
  • Female
  • Genotype
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Male
  • Mutation
  • Osteogenesis Imperfecta* / diagnosis
  • Osteogenesis Imperfecta* / genetics
  • Osteoporosis* / diagnosis
  • Osteoporosis* / genetics
  • Spinal Fractures*

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