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Conditions

Monogenic inflammatory bowel disease

For a small number of patients with inflammatory bowel disease, there may be a genetic cause that can influence management and treatment for the patient and their family.

Overview

Inflammatory bowel diseases (IBDs) are chronic relapsing immune-mediated conditions, primarily causing intestinal inflammation but also extraintestinal manifestations. IBD is usually caused by complex interactions between multiple genes and environmental factors and typically presents during adolescence or early adulthood.

In a small number of cases, often presenting during early childhood, single gene variants (mono- or bialleleic) can cause gut inflammation, often presenting with additional features, such as immunodeficiency. These monogenic forms of IBD often have specific management considerations and treatment implications.

Clinical features

When considering genomic testing for patients with IBD, the strongest association with a monogenic form is infantile age of onset: those with a disease onset by less than two years of age. If additional features are present, testing may be appropriate in those diagnosed between two and six years of age. Additional features suggestive of a potential monogenic IBD cause include immunodeficiency and/or inflammation or autoimmunity, congenital defects and early malignancy. Testing of older patients may be appropriate if there are extremely compelling reasons.

All patients must have a confirmed diagnosis of IBD prior to sending for genomic testing. In children, this should be a diagnosis in line with the modified Porto criteria.

General features of IBD include:

  • diarrhoea;
  • bloody stools;
  • abdominal pain; and
  • weight loss or poor growth.

Laboratory tests consistent with IBD include:

  • raised faecal calprotectin – interpret with care in children aged <6 years, as it will be raised in children without IBD;
  • raised inflammatory markers;
  • anaemia; and
  • hypoalbuminaemia.

When considering a potential diagnosis of monogenic IBD, there are specific additional features that may be indicative of a single-gene cause:

  • severe perianal disease;
  • infection susceptibility and results consistent with immunodeficiency;
  • inflammatory features – such as features of auto-inflammatory disorder;
  • congenital multiple intestinal atresias or congenital diarrhoea;
  • early-onset malignancy (<25 years of age);
  • severe treatment-refractory disease; and/or
  • extensive extra-intestinal manifestations (dermatological, liver and rheumatological).

Further information on specific criteria that must be established for genomic testing can be seen in the ‘Diagnosis’ section.

Genomics

To date, and as reported in Bolton and others, variants in around 100 genes have been demonstrated to cause monogenic forms of IBD. These genes are most commonly within immune pathways, or are important in maintaining epithelial barrier function. Currently, a slightly more limited number of genes, as listed on the NHS Genomic Medicine Service Signed Off Panels resource, are available for testing through the R15 panel.

The clinical picture for different presentations of monogenic forms of IBD may be extremely varied. It is important to acknowledge the variability between patients and conditions.

Diagnosis

When considering testing for monogenic forms of IBD, there are specific eligibility criteria that must be met prior to sending patients for testing. These genomic testing criteria are as follows (taken from Kammermeier and others):

  • Age of IBD onset:
    • under 2 years of age; or
    • under 6 years of age in the presence of one or more additional testing criteria (see below).
  • Infection susceptibility (recurrent sinopulmonary infections, systemic infections such as meningitis and/or sepsis, gastrointestinal infections, cutaneous infections) in the presence of abnormal laboratory tests (for instance congenital lymphopenia or neutropenia, or combined immunoglobulin level abnormalities) meeting diagnostic criteria of an inborn error of immunity (primary immunodeficiency).*
  • Inflammatory features indicative for an inborn error of immunity such as complex autoimmune features (especially features of immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome in the paediatric population or severe multi-organ autoimmune disease in the adult population) or haemophagocytic lymphohistiocytosis.
  • Congenital multiple intestinal atresias or congenital diarrhoea.
  • Early-onset malignancy (<25 years of age).
  • Family history of suspected monogenic IBD.

Supportive features that may trigger testing in specific cases:

  • family history (for instance consanguinity, which increases the chance of an autosomal recessive cause, or multiple affected family members so suggestive of a recessive, X-linked or highly penetrant dominant disorder);
  • failure to thrive/growth delay;
  • severe perianal disease and impaired wound healing; and/or
  • IBD refractory to multiple therapies.**

* Criteria not explained by immunosuppressive or immunomodulatory IBD medication.

** IBD refractory to multiple IBD therapies is a poorly defined term and in isolation should not trigger genetic screening, as the prevalence of monogenic IBD and the impact/benefit of clinical genomics in this cohort are unknown.

It is also important to consider genomic testing in advance of high-risk or irreversible interventions or therapies including haematopoietic stem cell transplantation.

Inheritance and genomic counselling

Most forms of monogenic IBD are autosomal recessive or X-linked; a small fraction is autosomal dominantly inherited. Once diagnosed, the patient/family should have appropriate genetic counselling. Genetic counselling should include consideration of the wider family, and if required genomic testing may be available for family members.

It should be acknowledged that monogenic causes of IBD are overall exceedingly rare, and many have recently been identified. In some cases, the long-term prognosis will be uncertain.

Importantly, identification of causative variants should highlight the need for monitoring of other specific features of disease, such as immunodeficiency or metabolic manifestations. These should be investigated, monitored and managed appropriately.

Autosomal recessive

Should an autosomal recessive cause be identified, parents may have genomic testing to see if they are carriers. If both parents are carriers of an autosomal recessive condition, they would be counselled that with each pregnancy there is a:

  • 1 in 4 (25%) chance of a child inheriting both gene copies with the pathogenic variant and therefore being affected;
  • 1 in 2 (50%) chance of a child inheriting one copy of the gene with the pathogenic variant and one normal copy, and therefore being a healthy carrier themselves; and
  • 1 in 4 (25%) chance of a child inheriting both normal copies and being neither affected nor a carrier.

Reproductive options are available, including testing in early pregnancy or pre-implantation genetic testing, which is an IVF-based technique in which embryos without specific genetic variants are transferred. Consideration should also be given to existing siblings.

X-linked

If an X-linked cause is identified in a male patient, then their mother would be offered genomic testing. If she is found to be a carrier, she would be counselled as below. Again, reproductive options are available.

  • X-linked recessive conditions are usually only present in males.
  • Males with X-linked conditions cannot pass the variant on to their sons, but they always pass their affected X chromosome to their daughters. If the condition is recessive, their daughters will be carriers for the condition.
  • Female carriers of X-linked recessive conditions have a second, working copy of the gene and are therefore usually unaffected, or affected only mildly.
  • Sons of female carriers of X-linked recessive conditions have a 1 in 2 (50%) chance of being affected by the condition, and their daughters have a 1 in 2 (50%) chance of being carriers.

Autosomal dominant

If an autosomal dominant cause is identified it should be established whether this is a new (de novo) variant in the patient, or whether it has been inherited from an affected parent. Some variants have variable expressivity which means the condition can present differently in family members. If the latter is found, then the parents would be counselled as below.

  • Individuals affected by an autosomal dominant condition have one working copy of the gene, and one with apathogenic variant.
  • The chance of a child inheriting the gene with the variant from an affected parent is 1 in 2 (50%).
  • Incomplete penetrance can occur when not everyone who has the variant develops the disease.

The future reproductive implications for the patient should also be considered and discussed. Many patients will be young at diagnosis; however, it is important to flag this as patients and their family will need to be aware if there is a need to seek reproductive advice in the future.

Management

The management implications for patients diagnosed with a monogenic form of IBD are specific to the genetic variant. Haemopoietic stem-cell transplantation is a treatment option in a number of genomic causes, including the IL10-pathway defects, defects in CYBB or CYBA and XIAP, plus selected other conditions.

For other genetic variants, such as those in SYK or TTC7A medication may prove beneficial. In other causes, conventional treatment with IBD therapeutics, such as 5-ASA, thiopurines and monoclonal therapies, is indicated, although a case-by-case discussion should occur for all individuals.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 28/02/2025
  • Next review due: 28/02/2027
  • Authors: Dr James Ashton, Professor Holm Uhlig
  • Reviewers: Dr Laura Kelly, Dr Joanna Kennedy