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Example clinical scenario

A 15-year-old girl presents symptomatically with diabetes. Her father was diagnosed with glycosuria and subsequently confirmed to have diabetes at the age of 25. He has a BMI of 25, has been continually insulin treated since diagnosis, and had a myocardial infarction (MI) at the age of 46. The girl’s paternal grandmother was diagnosed with diabetes in her 30s and has been well managed on low doses of sulphonylureas.

When to consider genomic testing

  • If diabetes is diagnosed in a child or adolescent with a parent and grandparent who also have diabetes, there is a possibility of an underlying genetic cause, which could be the result of a change in a single gene (monogenic). Further investigation should be considered for:
    • individuals with diabetes diagnosed young and a child BMI below the 95th centile, who are unlikely to have type 1 diabetes because they are not on insulin treatment; and
    • individuals on insulin with negative autoantibodies (GAD, IA2A and ZnT8), a random non-fasting C-peptide value lower than 200 picomoles per litre (pmol/L) and a parent with diabetes, or a parent with maturity onset diabetes of the young (MODY) probability score lower than 20% if not insulin treated and lower than 10% if insulin treated (see the MODY calculator).
  • HNF1A MODY is one of the most common causes of monogenic diabetes and, as it typically presents in teenagers or young adults, is often initially misdiagnosed as type 1 diabetes.

What do you need to do?

  • Check the current guidelines for genomic testing in MODY and refer patients who meet the criteria.
  • 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.
  • To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
  • In cases that are close to diagnosis, you should test three pancreatic antibodies (GAD, IA2 and ZnT8) to help distinguish those with familial type 1 diabetes. This is because antibody positivity supports a diagnosis of autoimmune type 1 diabetes, as opposed to monogenic diabetes.
  • As the relevant tests are DNA-based, an EDTA sample is required.
  • If molecular genomic testing confirms a diagnosis of HNF1A MODY, arrange testing for other family members with diabetes.
  • HNF1A MODY can result in increased cardiovascular risk with early MI, despite ‘normal’ high-density lipoprotein (HDL) levels (the HDL is typically large and buoyant and non-cardio-protective).
  • Those with HNF1A MODY have a low renal threshold for glucose, and glycosuria is common, often presenting before the diabetes diagnosis.
  • HNF1A MODY is best treated with low doses of sulphonylureas, as affected individuals are sulphonylurea-sensitive.
  • 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.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 19/02/2024
  • Next review due: 19/02/2025
  • Authors: Professor Maggie Shepherd
  • Reviewers: Dr Kevin Colclough, Dr Asma Hamad