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At a glance:

  • Diabetes diagnosed in an individual who is under 25 and has a parent or child with diabetes raises the possibility of an underlying genetic cause, which could be a result of a change in a single gene (monogenic diabetes).
  • HNF1A maturity onset diabetes of the young (MODY) is one of the most common causes of monogenic diabetes, accounting for about 50% of cases. Because it typically presents in teenagers and young adults, it is often initially misdiagnosed as type 1 diabetes.
  • HNF1A MODY follows an autosomal dominant inheritance pattern, meaning that first-degree relatives have a 50% chance of being affected.
  • Alert! Testing three pancreatic antibodies (GAD, IA2 and ZnT8) close to diagnosis can help distinguish those with familial type 1 diabetes from those with HNF1A MODY. This is because antibody positivity supports an autoimmune type 1 diabetes diagnosis rather than a diagnosis of monogenic diabetes.

Example clinical scenario

A 24-year-old woman presents with diabetes with polydipsia, polyuria, glycosuria and a haemoglobin A1C (HbA1c) of 58 millimoles per mole (mmol/mol). She is otherwise fit and healthy, with a BMI of 23. She mentions that her father was diagnosed with diabetes at the age of 25, that he was insulin treated and that he had a myocardial infarction (MI) at the age of 50. In addition, her paternal grandmother was diagnosed with diabetes at the age of 32 and was treated with oral medication.

Identifying those at risk of a genetic condition

Flags for an underlying genetic diagnosis of HNF1A MODY are listed below.

  • Diagnosis of diabetes in an individual who is under 25 and has a parent or child with diabetes (typically three or more generations affected) in an autosomal dominant inheritance pattern.
  • Several family members diagnosed young who do not require insulin treatment or have evidence of endogenous insulin production – for example, they are C-peptide positive for more than three years post-diagnosis.
  • Evidence of sensitivity to sulphonylureas in other family members with diabetes, such as hypoglycaemia on standard doses (individuals with HNF1A MODY are sensitive to sulphonylureas).
  • Family history of early, possibly fatal MI:
    • HNF1A MODY can result in increased cardiovascular risk with early MI, despite ‘normal’ high-density lipoprotein (HDL) levels (the HDL is typically large, buoyant and non-cardioprotective).
  • Negativity of all three pancreatic antibodies (GAD, IA2 and ZnT8).
  • Evidence of low renal threshold for glucose (those with HNF1A MODY have a low renal threshold for glucose, and glycosuria is common – often presenting before the diabetes diagnosis).

What do you need to do?

  • Enquire about family history: ask particularly about any evidence of sulphonylurea sensitivity in other family members.
  • Enter the patient’s details into the MODY probability calculator.
  • Test for all three pancreatic antibodies (GAD, IA2 and ZnT8) in insulin-treated individuals and, if negative, refer for genomic testing.
  • If molecular genomic testing confirms a diagnosis of HNF1A MODY, arrange testing for other family members with diabetes.
  • HNF1A MODY is best treated with low doses of sulphonylureas. Insulin is typically not required, although a background dose of insulin in addition to oral medication may be needed in those with a long diabetes duration, because the diabetes is progressive.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.
  • Information about patient eligibility and test indications were 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

References:

For patients

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  • Last reviewed: 26/07/2023
  • Next review due: 26/07/2024
  • Authors: Dr Maggie Shepherd
  • Reviewers: Dr Kevin Colclough, Dr Amy Frost, Dr Asma Hamad