Monogenic Diabetes (Draft)
Overview
Monogenic diabetes is an inherited type of diabetes where a pathogenic variant in a single gene causes diabetes. It affects about 2-5% of people with diabetes, and many of these patients are often incorrectly diagnosed as having type 1 or type 2 diabetes (1).
The subtypes of monogenic diabetes most commonly diagnosed in the UK have an autosomal dominant pattern of inheritance where first-degree relatives have a 50% chance of inheriting the variant and being affected. Monogenic diabetes can be broadly split into three categories:
- Neonatal diabetes diagnosed under 6 months of age.
- MODY (Maturity onset diabetes of the young) characterised by non-syndromic diabetes without features of autoimmunity or insulin resistance that typically presents between the ages of 10 and 30 years.
- Syndromic diabetes that can be diagnosed in neonatal, paediatric or early adult ages and is characterised by diabetes and additional extra-pancreatic features (e.g. deafness, neurological problems, structural renal disease) as part of a genetic syndrome.
The severity of monogenic diabetes is variable and it can be associated with other problems, e.g. with kidneys or liver, deafness, increased risk of early IHD etc.
Who to Refer
Enquire about family history, including whether diabetes was diagnosed incidentally in other family members and their HbA1c levels if known.
Enter details into the MODY probability calculator ( link provided by Exeter Diabetes App):
Exeter Diabetes App (diabetesgenes.org)
The calculator gives a risk score and appropriate next steps. Consider referring for testing where probability is >20%.
A number of key features make a diagnosis of monogenic diabetes more likely:
- Young age of onset; typically before the age of 35 years or diagnosed in the first 6 months of life
- A less severe diabetes presentation with absence of ketoacidosis and HbA1c <7.5% at diagnosis
- Diabetes identified in two or more generations
- A normal BMI and absence of features associated with metabolic syndrome
- Absence of islet-autoantibodies
- Not insulin dependent (not insulin treated or C-peptide is detectable outside of the usual honeymoon period)
- Asymptomatic persistent fasting hyperglycaemia and stable but mildly raised HbA1c that does not change with treatment
- History of newborn macrosomia and neonatal hypoglycaemia in the family
- Sensitivity to sulphonylureas (low doses result in significant improvement in control or hypoglycaemia)
- Additional developmental problems suggestive of a genetic syndrome.
What to do before referral
Investigations in primary care if appropriate:
- C-peptide can be requested on ICE at both UHBW and NBT (but restrictions apply (e.g - for hypoglycaemia screen or transplant patients only- so not sure if this will be accepted)
- Pancreatic islet cell antibody test can be requested only via NBT ICE.
Before referral for genetic testing for monogenic diabetes, consider the eligibility criteria below:
Guidelines for Genetic Testing in MODY // Diabetes Genes
Genetic testing should be offered to all children diagnosed with diabetes that are negative for islet-autoantibodies and are not insulin treated/have detectable C-peptide.- children will normally be under secondary care team so is this relevant to primary care?
For insulin treated adult patients with a suspicion of monogenic diabetes and diabetes duration is >3 years, request a random non-fasting C-peptide test initially, and genetic test if C-peptide >200pmol/L - Can GPs request this locally? - See comment about C-Peptide above.
Referral
The Exeter Genomics Laboratory at the Royal Devon & Exeter Hospital is the national specialist provider for all monogenic diabetes testing in England.
Referrals directly from GPs are accepted and do not require referral to clinical genetics or a secondary care consultant since the laboratory will determine suitability for testing and provide guidance if a genetic diagnosis is made. Referral to secondary care can then be made as appropriate. Testing is centrally funded by NHSE for patients meeting eligibility criteria; there is no charge to the GP or ICB.
Please complete a MODY genetic testing referral form which can be found on the link below:
Diabetes Genes > Information for patients and professionals on genetic types of diabetes > Genetic Test Referral Forms (this form has Exeter details on it and not Bristol Genomics lab)
This should be sent with a 3-5ml of EDTA whole blood to the Bristol Genomics Laboratory for processing (Where is Bristol Genomics lab based? Is this just sent in a normal blood bag to local path lab - will it find it's way to the appropriate department in BNSSG) Slide 1 (nbt.nhs.uk)
If molecular genetic testing confirms a diagnosis of monogenic diabetes, arrange genetic testing for other family members with a diabetes diagnosis as this may alter their treatment. The Exeter Genomics Laboratory can provide assistance with this through provision of ‘at-home’ self-collection kits for capillary blood; contact rduh.betacellgenomics@nhs.net for details.
First degree relatives not known to have diabetes can be offered pre-symptomatic testing but this requires genetic counselling so the individual can decide whether or not to proceed.
Alert! There are different implications for testing family members depending on the gene affected so specialist advice should be sought from the Exeter team: m.shepherd1@nhs.net
Resources
(3) HEE GEP GeNotes GeNotes: Genomic notes for clinicians | GEP | Health Education England | NHS (hee.nhs.uk)
(4) How do I diagnose Maturity Onset Diabetes of the Young in my patients? - PMC (nih.gov) Colclough K, Patel K. Clin Endocrinol (Oxf). 2022 Oct;97(4):436-447