Presentation: Infant with features of very early-onset inflammatory bowel disease

A six-month-old boy is referred to paediatrics with a two-month history of diarrhoea, occasionally with blood and mucus. He has a past history of a perianal abscess, which required emergency incision and drainage last month.

Genomic testing should be considered if a gastroenterologist, paediatric gastroenterologist or immunologist suspects monogenic inflammatory bowel disease (IBD). Typically, this will include the following presentations;

• infantile-onset IBD (<2 years of age); or
• very early-onset IBD (<6 years of age) with a severe course, such as requirement for biologics and/or surgery, or relevant comorbidities and extra-intestinal manifestations.

Testing may occasionally be appropriate outside these criteria and should be discussed in a relevant multidisciplinary meeting. For example, paediatric or young adult IBD with documented severity criteria, such as relevant family history, comorbidities and extraintestinal manifestations, such as infection susceptibility.

For acutely unwell children and adults, where testing may provide an immediate change to treatment or clinical management for the patient, semi-rapid testing is available.

If IBD is part of a broader syndromic diagnosis, alternative broader genomic testing should be considered.

• 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.
• Decide which of the panels best suits the needs of your patient and/or family.
• For suspected monogenic IBD:
  • R15 Primary immunodeficiency diseases or monogenic inflammatory bowel disease (whole genome sequencing (WGS)). This will investigate exon-level copy number variants, smaller variants and single gene causes of monogenic IBD, immunodysregulation and/or autoinflammation. The test involves a WGS panel of many genes known to cause immunodeficiency, immunodysregulation, auto inflammation and hemophagocytic lymphohistiocytosis (HLH).
• For acutely unwell children and adults with suspected monogenic IBD where testing may provide an immediate change to treatment or clinical management for the patient, semi-rapid testing is available via the clinical indication R15. Please indicate the presentation on the request form as applicable. Testing under this indication must be pre-authorised.
• If IBD is part of a broader syndromic diagnosis, broader genomic testing should be considered.
  • In a non-urgent setting, this could include requesting R27 Paediatric disorders, in combination with R15.
    • R27 is an amalgamation of more than 10 panels of genes known to be associated with a broad range of paediatric developmental conditions. It may now be ordered directly by paediatricians, though a discussion with clinical genetics services may be beneficial.
  • In an urgent setting, R14 Acutely unwell children with a likely monogenic disorder may be most appropriate.
    • R14 requests currently require authorisation from a clinical genetics team.
    • There is a special test order form and record of discussion (RoD) form for R14, which are available from the Exeter Clinical Laboratory.
• Note that other more targeted tests may be appropriate for patients with suspected early-onset IBD with specific features:
  • R17 Lymphoproliferative syndrome with low or absent SAP expression: This should be used in individuals with absent SAP expression, and involves SH2D1A gene analysis;
  • R18 Lymphoproliferative syndrome with low or absent XIAP expression: This should be used in individuals with absent XIAP expression, and involves a XIAP gene test and multiplex ligation-dependent probe amplification (MLPA);
  • R233 Agammaglobulinaemia with low or absent BTK expression: This should be used in individuals with absent BTK expression, and involves a BTK gene test and MLPA;
  • R20 Wiskott-Aldrich syndrome: This should be used in individuals with a likely diagnosis of Wiskott-Aldrich syndrome (WAS) and involves a WAS gene test; and
  • R157 Immunodysregulation polyendocrinopathy and enteropathy, X-linked (IPEX): This should be used in those with a likely diagnosis of IPEX, and involves a FOXP3 gene test.
• For tests that do not include WGS, including R17, R18, R20, R157 and R233:
  • you can use your local Genomic Laboratory Hub test order and consent (RoD) form; 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 and R27, 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

• Crohn’s & Colitis Foundation: Very early onset inflammatory bowel disease work up (PDF, 8 pages)
• 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
• Nambu R, Warner N, Mulder DJ and others. ‘A systematic review of monogenic inflammatory bowel disease‘. Clinical Gastroenterology and Hepatology 2022: volume 20, issue 4, pages e653–e663. DOI: 10.1016/j.cgh.2021.03.021

For patients

• Crohn’s & Colitis Foundation: Very early onset inflammatory bowel disease work up (PDF, 8 pages)
• Immunodeficiency UK
• Jeffrey Modell Foundation