Presentation: Child with agammaglobulinaemia with absent BTK expression

A two-year-old boy is referred to paediatrics with a history of recurrent pneumonia since he was six months of age. He also has chronic otitis media. Blood tests have showed undetectable levels of serum immunoglobulins (IgG, IgA and IgM) with <1% B cells. His family history is notable for his maternal grandfather having long-standing bronchiectasis and recurrent chest infections.

Genomic testing with R233 should only be undertaken if the patient is suspected to have X-linked agammaglobulinaemia based on:

• typical clinical features of the disease; with
• low or absent Bruton tyrosine kinase (BTK) expression; or
• absent B cells in male patients.

R15 should be used if the broader diagnosis of agammaglobulinaemia and/or immunodeficiency is suspected.

R233 and R15 testing should typically be requested by immunology or clinical genetics teams.

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria, which contains information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details 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.
• For patients with suspected X-linked agammaglobulinaemia with low or absent BTK expression, consider:
  • R233 Agammaglobulinaemia with absent BTK expression (single gene sequencing of BTK).
• For conditions in which the broader diagnosis of agammaglobulinaemia and/or immunodeficiency is suspected, consider:
  • R15 Primary immunodeficiency. This will investigate causes of severe combined immunodeficiency. The test includes a whole genome sequencing (WGS) panel of all genes known to cause immune conditions.
• For tests that do not include WGS, including R233:
  • you can use your local Genomic Laboratory Hub test order and consent (record of discussion (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.
• For tests that are undertaken using WGS, including R15, 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 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 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. There are a few tests for which a different type of tube is used; 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

• European Society for Immunodeficiencies: Diagnostic criteria PID
• Jeffrey Modell Foundation: 10 warning signs of primary immunodeficiency

References:

• Bousfiha A, Moundir A, Tangye SG and others. ‘The 2022 Update of IUIS Phenotypical Classification for Human Inborn Errors of Immunity‘. Journal of Clinical Immunology 2022: volume 42, issue 7, pages 1,508–1,520. DOI: 10.1007/s10875-022-01352-z
• El-Sayed ZA, Abramova I, Aldave JC and others. ‘X-linked agammaglobulinemia (XLA): Phenotype, diagnosis, and therapeutic challenges around the world‘. World Allergy Organization Journal 2019: volume 12, issue 3. DOI: 10.1016/j.waojou.2019.100018

For patients

• Immunodeficiency UK
• Jeffrey Modell Foundation
• XLA Life