Genetic Testing for Diabetes Presenting in Infancy

A new type of insulin dependent diabetes in children diagnosed under 6 months that may alter treatment.

The genetic team lead by Professor Andrew Hattersley in Exeter have recently identified that activating mutations in the Kir6.2 gene cause diabetes and typically this is diagnosed in the first six months of life (Gloyn et al. N Eng J Med 2004:350; 1838-1849). These patients were normally de-novo mutations and so did not have diabetic relatives. However, around 10% showed generation to generation transmission with an autosomal dominant inheritance and about 20% of patients had neurological features, typically developmental delay and in some cases epilepsy. Beta-cell autoantibodies seen in Type 1 diabetes were not detected. They usually presented with very high glucose values and occasionally ketoacidosis and often C peptide was not measurable even in response to either glucose or glucagon. However, these patients did show an insulin secretory response to intravenous tolbutamide (a sulphonylurea) suggesting this might offer a new treatment approach.

To date, at least 50 patients have since been successfully treated with oral sulphonylurea tablets (stopping insulin completely with better control and less hypos) despite being apparently insulin dependent. Reports of this include:

1. Klupa T, et al. Diabetologia. 2005 May; 48(5):1029-31
2. Codner E, et al. Diabetes Care. 2005 Mar; 28(3)758-9
3. Zung A. J Clin Endocrinol Metab. 2004 Nov; 89(11):5504-7
4. Sagen JV, Diabetes. 2004 Oct; 53(10):2713-8

Seven patients have not managed to transfer from insulin. Most of these have had very severe neurological features with profound developmental delay and generalised epilepsy before 6 months or were adults when the change of therapy was introduced.

Which patients could be tested?

We would be interested in providing diagnostic testing for all patients diagnosed with diabetes under the age of 6 months whatever their age now. This is provided free of charge as it is funded by research funding. Mutations were found in around 35-50% of those tested diagnosed before 6 months. Specific features that increase the chance of diagnosis are: low birth weight 1.8 - 3.1kg at term, a family history of neonatal diabetes or marked developmental delay, but the latter 2 features were only seen in a few cases. The present age of the patient is not important and patients diagnosed in the first six months of life who are now under the adult physicians would be appropriate for testing.

We would strongly recommend taking blood or DNA from both parents as well as the child, as this will allow us to establish rapidly that a genetic mutation is likely to be the cause of the diabetes if it has risen de novo and is not present in either unaffected parent.

Details to send with samples

Please when you send us a sample for genetic testing, please send us all details on our request form. These include:

Referring clinician details
Patient Details
General
Presentation
Current status of Patient
Any other clinical features

Consent

When taking samples you should get written consent for the testing - as with any genetic test. You can download the consent form that you might like to use, modify, or translate. We ask you get consent from the patient/parents to test for the genetic cause of the patient's diabetes rather than limiting to Kir6.2.

Samples to be taken

The samples should be labelled with name and date of birth and can either be:

1. Our preferred option is Blood 3-5mls: taken in tubes containing EDTA and couriered fresh (not frozen). Must arrive in UK within 5 days, so ideally send on a Monday. This should be sent in a package with at least two layers of wrapping and include absorbent material to absorb any blood that leaks out of the tube.
2. Or made into DNA in your own country and 2-10 micrograms (to allow repeats) sent at room temperature. Again please make sure the tube is very securely sealed.

Where should the sample be sent?

Please e-mail the patient’s name and date of birth to rh8.MolecularGenetics@nhs.net together with the completed request form and/or additional clinical details. The details will be pre-logged so that when the samples arrive we can match up the information and send you an e-mail confirming sample receipt.

The sample should be sent to:

Prof. Sian Ellard PhD FRCPath
Consultant Molecular Geneticist
Molecular Genetics Laboratory
Royal Devon and Exeter NHS Healthcare Trust
Barrack Road
Exeter, EX2 5AD
UK

Tel: +44 1392 402910
Email: Sian.Ellard@rdeft.nhs.uk

Confidentiality

We put these samples through diagnostic procedures and so deal with them as diagnostic samples and hence do use names and dates of birth to give us 2 identifiers on each sample. This information is then dealt with in complete confidentiality. This means we issue a report with the patient's name and date of birth on it that can join their clinical records while an anonymous one could not. Using the patients' names also prevents the same patient being referred by more than one clinician although this is unlikely to be a problem. We would request that a sample comes with a name and date of birth so it can enter our system and we can always find the sequence etc. if there are any queries. Our lab is dealing with approximately 50 diagnostic DNA samples a day and full confidentiality has to be maintained for all of these so this is not an issue.

Results

We will send a result as soon as possible, usually by email. Samples from newly diagnosed babies are prioritised for testing and a result is often available within 1 to 2 weeks. All physicians referring patients will receive a written report 6-8 weeks after the receipt of the sample. With mutations that have not previously been described, it is hard to be certain if they are pathogenic. This would be established if the mutation is not present in unaffected parents or by co-segregation with neonatal diabetes in families with multiple affected members. This is why we are keen to have DNA from both parents with the initial sample sent.

Other genes

If we do not find a Kir6.2, SUR1 or INS mutation we will test other known and possible causes of neonatal diabetes and will inform the physician if we find a positive result.

Download ISPAD Guidelines on the diagnosis and management of monogenic diabetes in children

Diabetes Genes

Search