Osteogenesis Imperfecta and Low Bone Density Panel, Sequencing

  • Use to confirm a clinical diagnosis of OI or monogenic cause of low bone density.
  • Do not order this test to confirm a diagnosis of hypophosphatemic rickets or osteopetrosis.
  • Regions of low coverage and reported variants are confirmed by Sanger sequencing as necessary.
Related Tests
  • Use to confirm diagnosis of a skeletal dysplasia in a symptomatic individual.
  • Use to determine the causative gene variant(s) in an affected individual.
  • Use to confirm diagnosis of a skeletal dysplasia in a symptomatic fetus.
  • Use to determine if a fetus at risk for a skeletal dysplasia based on a positive family history is affected.
  • Recommended test for a known familial sequence variant previously identified in a family member.
  • A copy of the family member’s test result documenting the familial variant is required.

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
Phenotype-Based Classification System for COL1A1- and COL1A2-Related OI
  Severity Features

Type I

Classic nondeforming (mild)

Predisposition to fractures

Blue sclera

Rarely DI

50% have hearing loss

Bone density can be normal

Type II

Perinatal lethal

Severe skeletal deformities

Severe short stature

DI

Type III

Severe progressively deforming

Very short stature

DI

Blue sclera

Hearing loss frequent

Type IV

Mild to moderate

Variable short stature

Mild to moderate bone deformities

Multiple fractures

Normal to gray sclera

Some with hearing loss

Some with DI

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 ~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

Analytical 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

Gene MIM Number Associated Disorders Inheritance

ALPL

171760

Hypophosphatasia, adult

AD/AR

Hypophosphatasia, infantile

Hypophosphatasia, childhood

AR

ANO5

608662

Gnathodiaphyseal dysplasia

AD

BMP1

112264

OI, type XIII

AR

CASR

601199

Hyperparathyroidism, neonatal severe

AD/AR

CLCN5

300008

Hypophosphatemic rickets

Dent disease 1

XLR

COL1A1

120150

Caffey disease

OI types I, II, III, and IV

Ehlers-Danlos syndrome, Arthrochalasia type 1

AD

COL1A2

120160

OI, Types II, III, and IV

Ehlers-Danlos syndrome, Arthrochalasia type 2

AD

CREB3L1

616215

OI, type XVI

AR

CRTAP

605497

OI, type VII

AR

CYP27B1

609506

Vitamin D hydroxylation-deficient rickets, type 1A

AR

FKBP10

607063

Bruck syndrome 1

OI, type XI

AR

GORAB

607983

Geroderma osteodysplasticum

AR

IFITM5

614757

OI, type V

AD

LRP5

603506

Endosteal hyperostosis, AD

Osteoporosis

Van Buchem disease, type 2

Osteopetrosis, AD 1

AD

Osteoporosis-pseudoglioma syndrome

AR

Exudative vitreoretinopathy 4

AD/AR

P3H1

610339

OI, type VIII

AR

P4HB

176790

Cole-Carpenter syndrome 1

AD

PLOD2

601865

Bruck syndrome 2

AR

PLS3

300131

Bone mineral density quantitative trait locus 18

AR

PPIB

123841

OI, type IX

AR

SEC24D

607186

Cole-Carpenter syndrome 2

AR

SERPINF1

172860

OI, type VI

AR

SERPINH1

600943

OI, type X

AR

SLC34A3

609826

Hypophosphatemic rickets with hypercalciuria, hereditary

AR

SP7

606633

OI, type XII

AR

SPARC

182120

OI, type XVII

AR

TMEM38B

611236

OI, type XIV

AR

WNT1

164820

OI, type XV

AR

XLR, X-linked recessive