Presentation: Clinical suspicion of ataxia telangiectasia

A family attends clinic concerned because their two-year-old daughter has had a progressively unsteady (ataxic) gait since she started walking. She has previously had two episodes of pneumonia, which required hospital admission.

• Genomic testing should be considered when a patient presents with clinical features strongly suggestive of ataxia telangiectasia, including elevated serum alpha fetoprotein (AFP) levels (usually unmeasurable in childhood) and one or more of the following:
  • progressive gait and truncal ataxia with onset between one and four years of age;
  • ocular motor apraxia;
  • ocular telangiectasia;
  • chorea and dysarthria;
  • immunodeficiency with frequent infections; and/or
  • malignancy (such as leukaemia, lymphoma, breast cancer, ovarian cancer, gastric cancer, leiomyoma, sarcoma or melanoma).
• For more detailed information on clinical features, see our Knowledge Hub resource, Ataxia telangiectasia.

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria for information about individual tests and their associated eligibility criteria. You can also access a spreadsheet of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see Genomic testing in the devolved nations.
• For information about the genes that are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• Decide which of the panels best suits the needs of your patient or family.
  • There are a number of tests that include the ATM gene affected in ataxia telangiectasia. The best option will depend on the signs and symptoms of your patient and whether you feel broad or specific genetic testing is indicated.
• If the presentation is less specific and you want to cover other causes of (for example) developmental delay you may wish to request:
  • R27 Paediatric disorders: This broad test investigates chromosomal and single-gene causes of developmental delay, intellectual disability and/or congenital abnormalities. This is a whole genome sequencing (WGS) panel with analysis of many genes known to cause genetic conditions in childhood.
  • R27 is an amalgamation of over 10 panels of genes known to be associated with a broad range of paediatric developmental disorders. It may now be ordered directly by paediatricians, though a discussion with clinical genetics services may be beneficial.
• If the presentation is very suggestive of ataxia telangiectasia with raised serum AFP levels, you may wish to request:
  • R294 Ataxia telangiectasia – DNA repair testing: This option involves DNA repair defect testing.
    • A lithium heparin sample is required, and should arrive within 72 hours, preferably 24 hours, of sampling. The samples should neither be spun down nor frozen prior to sending. Pre-warn your local lab to ensure prompt retrieval of the sample.
• If DNA repair testing, such as via R294, confirms the diagnosis you may then request:
  • R295 Ataxia telangiectasia – variant testing: This looks for the underlying genetic variant causing ataxia telangiectasia.
• These tests (R294 and R295) are typically requested by oncology, clinical genetics, haematology, immunology or neurology.
• Several other test options include analysis of ATM and may be appropriate for certain presentations with a narrow differential. Requesting these may require a paediatric subspecialist (such as paediatric neurology) or alternative specialty (such as dermatology or immunology), or a discussion with clinical genetics. These other test options include:
  • R55 Hereditary ataxia with onset in childhood: This investigates unexplained hereditary ataxia with onset in childhood. It includes a WGS panel.
  • R57 Childhood onset dystonia, chorea or related movement disorder: This investigates dystonia, chorea and/or movement disorder. It includes a WGS panel.
  • R15 Primary immunodeficiency or monogenic inflammatory bowel disease: This investigates suspected immunodeficiency diagnosed by a consultant immunologist. It includes a WGS panel.
  • R326 Vascular skin disorders: This investigates vascular skin disorders with a likely germline genetic cause. It includes whole exome sequencing (WES) or a medium panel of genes.
• For tests that do not include WGS, including R294 and R295:
  • you can use your local Genomic Laboratory Hub (GLH) test order and consent (record of discussion) 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.
• For tests that are undertaken using WGS, including R27, R55, R57, R15 and R326, you will need to:
  • complete an NHS GMS test order form with details of the affected individual (proband) and their parents where available, 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); and
  • 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 individual and their parents, you will need three RoD forms (see How to complete a RoD form for support);
  • obtain a consultee form signed by an appropriate relative or advocate if an adult patient does not have capacity to consent to genomic testing; and/or
  • submit parental samples alongside the child’s sample 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).
• Most tests are DNA based, and an EDTA sample (typically a purple-topped tube) is required. Exceptions include karyotype testing and DNA repair defect testing (for chromosome breakage), which require lithium heparin (typically a green-topped tube). For more information, see Samples for genomic testing in rare disease.
• If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.
• 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 clinicians

• GeneReviews: Ataxia-telangiectasia
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory

References:

• Firth HV and Hurst JA. ‘Oxford Desk Reference: Clinical Genetics and Genomics (second edition)’. Oxford University Press 2017, page 399. DOI: 10.1093/med/9780199557509.003.0003
• van Os NJH, Haaxma CA, van der Flier M and others. ‘Ataxia-telangiectasia: Recommendations for multidisciplinary treatment’. Developmental Medicine & Child Neurology 2017: volume 59, issue 7, pages 665–770. DOI: 10.1111/dmcn.13424

For patients

• AT Society
• Contact a Family: Ataxia telangiectasia
• NHS Health A to Z: Types of ataxia