Presentation: Clinical suspicion of osteogenesis imperfecta

A seven-year-old boy presents with a fractured tibia after a fall off his scooter. He has had two previous long bone fractures with minimal trauma. His mother had multiple fractures as a child but has had none since. On examination, his height is two standard deviations (2SD) below the mean (on the 2nd centile) and he has joint hypermobility.

You should consider genomic testing if your patient has features suggestive of osteogenesis imperfecta (OI). In adults, testing is only routinely recommended if it will impact on reproductive choices. In general, testing should only be performed if it will impact clinical management.

Features of OI may include:

• fractures (associated with minimal or no trauma);
• short stature;
• bowing of long bones;
• blue sclera;
• abnormal dentition (dentinogenesis imperfecta);
• hypermobility; and
• hearing loss (post-pubertal).

Radiological features include:

• fractures;
• wormian bones;
• ‘codfish’ vertebrae;
• low bone mass; and
• protrusio acetabuli.

• If you clinically suspect OI in a family, the correct test to order is:
  • R102 Osteogenesis imperfecta: This is a multi-gene panel and includes whole exome sequencing or a medium panel and multiplex ligation-dependent probe amplification (MLPA) to look for exon level copy number variants.
• If a member of the family already has a known OI-related gene causative variant, cascade testing can be carried out to identify other affected individuals. Testing relatives when the molecular basis is confirmed in the family may not be needed unless there is a clear rationale for doing so – for example, where the clinical diagnosis in the relative is in doubt, or if testing the relative will lead to a clear benefit in management, such as eligibility for a clinical trial. In this situation, the laboratory will test for the known familial variant only. First-degree relatives may be eligible for genomic counselling, at which point subsequent testing (R240 Diagnostic testing for known mutation(s)) can be arranged.
• If you feel there are other likely diagnoses for bone fragility, or if R102 testing is negative, you may wish to consider the following tests:
  • R104 Skeletal dysplasia: This should be considered if clinical features are indicative of a likely monogenic skeletal dysplasia. See A child with suspected skeletal dysplasia.
  • R28 Congenital malformation and dysmorphism syndromes (microarray only) or R27 Paediatric disorders if your patient has short stature and congenital malformations and/or dysmorphism suggestive of an underlying monogenic disorder, and targeted genomic testing is not possible.
  • Skin biopsy for collagen analysis can be useful if genomic testing is negative and the diagnosis is still unclear.
• Requesting either R104 or R27 – this latter one is a large whole genome sequencing (WGS) ‘super-panel’ – requires authorisation from clinical genetics. If discussed and accepted for testing, it is important to complete the correct forms. Both tests are undertaken through WGS, so you will need to:
  • complete an NHS Genomic Medicine Service (GMS) test order form with details of the affected child (proband) and their parents, including details of the phenotype (using human phenotype ontology (HPO) terms) and the appropriate panel name(s) with associated R number (see How to complete a test order form for WGS for support in completing WGS-specific forms);
  • complete an NHS GMS record of discussion (RoD) form for each person being tested – for example, if you are undertaking trio testing of an affected child and their parents, you will need three RoD forms (see How to complete a record of discussion form for support); and
  • submit parental samples alongside the child’s sample (this is trio testing) to aid interpretation, especially for the larger WGS panels (where this is not possible, for example because the child is in care or the parents are unavailable for testing, the child may be submitted as a singleton).
• For tests that do not include WGS, such as R102 and R28:
  • you can use your local Genomic Laboratory Hub test order and consent (RoD) forms; and
  • parental samples may be needed for interpretation of the child’s result. Parental samples can be taken alongside that of the child, and their DNA stored, or can be requested at a later date if needed.
• R102 and R28 are DNA-based tests, so an EDTA sample (purple topped tube) is required. Exceptions include karyotype testing and DNA repair defect testing (for chromosome breakage), which require lithium heparin (green-topped tube).
• Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.
  • For those working within NHS Wales, please consult the All Wales Medical Genomics Service website for information on how to arrange testing.

For clinicians

• GeneReviews: COL1A1/2 Osteogenesis imperfecta
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• National Organization for Rare Disorders: Osteogenesis imperfecta
• NHS England: National Genomic Test Directory
• Patient Info: Osteogenesis imperfecta
• Skeletal Dysplasia Group
• Skeletal Dysplasia Management Consortium: Publications

For patients

• Brittle Bone Society
• Osteogenesis Imperfecta Foundation