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, which provides information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details of all available tests.
  • For those working within NHS Wales, please consult the All Wales Medical Genomics Service website for information on how to arrange testing.
• To find out which genes 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 panels that include the ATM gene affected in ataxia telangiectasia. Where there is developmental delay or intellectual disability, paediatricians may request:
  • R29 Intellectual disability (microarray and sequencing): to investigate chromosomal and single-gene causes of developmental delay or intellectual disability. This includes microarray and a whole genome sequencing (WGS) panel of all genes known to cause intellectual disability.
• Several other test options are available for a suspicion of ataxia telangiectasia or related disorders, though requesting them 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:
  • R294 Ataxia telangiectasia (DNA repair testing): To be considered if there is a strong clinical suspicion of ataxia telangiectasia. This option involves DNA repair defect testing (a lithium heparin sample is required).
  • R295 Ataxia telangiectasia (mutation testing): To be considered if there is a confirmed clinical diagnosis of ataxia telangiectasia requiring direct gene testing. This option involves single gene sequencing.
  • R55 Hereditary ataxia and cerebellar anomalies (childhood onset): This investigates unexplained hereditary ataxia with onset in childhood. It includes short tandem repeat (STR) testing and a WGS panel.
  • R57 Childhood onset dystonia, chorea or related movement disorder: This investigates dystonia, chorea and/or movement disorder. It includes STR testing and 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 and may include multiplex ligation-dependent probe amplification (MLPA).
  • R359 Childhood solid tumours: This investigates solid tumours diagnosed in childhood where no other testing criteria are met. It includes WES or a medium panel of genes and may include MLPA.
  • R27 Congenital malformation and dysmorphism syndromes (microarray and sequencing): To be considered if there is developmental delay or intellectual disability in association with congenital malformation or overgrowth, and you would like to investigate potential chromosomal and single-gene causes. This option includes microarray and a WGS ‘super panel’ (a panel comprised of several different constituent panels forming one large panel).
• For tests that are undertaken using WGS, you will need to:
  • complete an NHS 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 child in care or the parents are unavailable for testing, the child may be submitted as a singleton).
• For tests that do not include WGS:
  • 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.
• The majority of tests are DNA-based, and 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).
• R27 is a large WGS ‘super panel’, and requesting it currently requires authorisation from clinical genetics.
• 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