Osteogenesis Imperfecta and Low Bone Density Panel, Sequencing

Polygenetic factors are responsible for 80% of bone mineral density. Although osteoporosis is present in 10% of the U.S. population, monogenetic causes of osteoporosis, such as osteogenesis imperfecta (OI), are rare. OI comprises a continuum of phenotypes ranging from individuals with perinatal lethal OI, severe skeletal deformities, dentinogenesis imperfecta (DI), and severe short stature to individuals with normal stature, dentition, and lifespan but with mild predisposition to fractures.

Disease Overview

Prevalence

6-7/100,000 for OI

Symptoms of Osteogenesis Imperfecta

• Predisposition to fractures, especially long bones, ribs, skull, spine
• Low bone mass or osteoporosis
• Skeletal deformities
• Variable DI
• Short stature
• Blue/gray scleral hue
• Joint hypermobility, early onset arthritis, scoliosis
• Progressive postpubertal mixed conductive/sensorineural hearing loss
• Protrusion acetabuli

Genetics

Genes

ALPL, ANO5, BMP1, CASR, CLCN5, COL1A1, COL1A2, CREB3L1, CRTAP, CYP27B1, FKBP10, GORAB, IFITM5, LRP5, P3H1, P4HB, PLOD2, PLS3, PPIB, SEC24D, SERPINF1, SERPINH1, SLC34A3, SP7, SPARC, TMEM38B, WNT1

Etiology

Pathogenic variants in collagen 1 genes, collagen 1 processing genes, and osteoblast genes

• Pathogenic COL1A1 and COL1A2 variants are causative for approximately 90% of OI.
• Pathogenic variants in more than 25 other genes are causative for rarer forms of OI or other monogenic forms of decreased bone density.

Inheritance

• 60% of mild and 100% of severe OI cases are caused by de novo variants or a pathogenic variant inherited from a parent with somatic and/or germline mosaicism.
• Parental germline mosaicism is present in up to 16% of families.
• COL1A1 and COL1A2 variants are autosomal dominant (AD), but variants in other causative genes may be autosomal recessive (AR), X-linked, or AD (see table of Genes Tested).

Penetrance

Varies depending on causative gene; complete for COL1A1 and COL1A2 variants

Test Description

Clinical Sensitivity 

OI: >90%

Other monogenic forms of osteoporosis or low bone density: unknown

Analytic Sensitivity

The analytical sensitivity of this test is approximately 99% for single nucleotide variants (SNVs) and greater than 93% for insertions/duplications/deletions from 1-10 base pairs in size. Variants greater than 10 base pairs may be detected, but the analytical sensitivity may be reduced.

Limitations

• A negative result does not exclude a diagnosis of OI or low bone density.
• Diagnostic errors can occur due to rare sequence variations.
• Interpretation of this test result may be impacted if the individual has had an allogeneic stem cell transplantation.
• The following will not be evaluated:
  • Variants outside the coding regions and intron-exon boundaries of targeted genes
  • Regulatory region and deep intronic variants
  • Large deletions/duplications
  • Noncoding transcripts
  • The following exons are not sequenced due to technical limitations of the assay:
    • LRP5 (NM_002335) exon 1
• The following may not be detected:
  • Deletions/duplications/insertions of any size by massively parallel sequencing
  • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
  • Low-level somatic variants

Genes Tested