Presentation: Infant with severe combined immunodeficiency with features of gamma chain deficiency (X-linked severe combined immunodeficiency)

A one-month-old boy has been referred to tertiary immunology services following a hospital admission for Pneumocystis jiroveci pneumonia. He was found to have T and NK cell lymphopenia, with B cells present. During the hospital admission, bloods demonstrated absent gamma chain expression and reduced STAT5 phosphorylation following cytokine stimulation. His mother is an only child, her two brothers having died in infancy due to sepsis.

Genomic testing with R235 should only be undertaken in males with T cell-negative, B cell-positive severe combined immunodeficiency (SCID) with low or normal NK cells with:

• low or absent gamma chain expression; or
• low or absent STAT5 phosphorylation to IL-2, IL-7 and IL-15.

R15 should be used if the broader diagnosis of SCID is suspected, without the specific features listed above.

R235 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.
• To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• For tests that do not include whole genome sequencing (WGS), including R235:
  • 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
• GeneReviews: X-linked severe combined immunodeficiency
• 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

For patients

• Immune Deficiency Foundation: Severe combined immunodeficiency (SCID)
• Immunodeficiency UK
• Jeffrey Modell Foundation