This test for 25 monogenic diabetes genes can be requested either as the first test (NHS price £650/non-NHS £812.50) or as a follow-on test (NHS price £300/non-NHS £375) after Sanger sequencing of the GCK or HNF1A/HNF4A genes. An online probability calculator can predict the likelihood of MODY according to a patient’s clinical characteristics. Please contact the Exeter team for advice regarding the best testing strategy for your patient (kevin.colclough@nhs.net or 01392 408324).
5-10ml venous blood in plastic EDTA bottles or >5µg DNA.
Our average reporting time for sequencing the GCK or HNF1A/HNF4A genes is 3 weeks. Next generation sequencing currently takes longer and the national target is 12 weeks. Future technological developments are expected to make testing faster and cheaper.
Potentially, yes. The test includes the LMNA gene in which mutations cause a range of phenotypes including partial lipodystrophy, Emery-Dreifuss muscular dystrophy, Charcot-Marie-Tooth disease type 2B, limb girdle muscular dystrophy type 1b, Hutchinson-Gifford Progeria syndrome and dilated cardiomyopathy. More than 200 patients with partial lipodystrophy have been tested in our laboratory and no mutations causing other phenotypes have been identified. Therefore the likelihood of finding a mutation that predisposes to, for example, dilated cardiomyopathy is low.
The test includes the ABCC8 and KCNJ11 genes since activating mutations cause sulphonylurea responsive diabetes. Congenital hyperinsulinism results from recessive inactivating ABCC8 and KCNJ11 mutations; carrier status for hyperinsulinism (identification of a heterozygous inactivating mutation) will not be reported.
This test will identify the same types of mutations detected by Sanger sequencing as well as large deletions or duplications previously identified by a separate dosage assay. The test sensitivity is estimated at >97.5% (95% CI). Balanced translocations, inversions and intronic mutations located outside splice sites will not be detected. There are some parts of the human genome that are not amenable to next generation sequencing, including a small part of the GATA6 gene. Mutations in GATA6 cause pancreatic agenesis with cardiac and other anomalies, but a few patients diagnosed with diabetes in adolescence/adulthood have been reported (De Franco et al 2012 Diabetes 62: 993-997) so this region will be analysed by Sanger sequencing for patients with a cardiac abnormality.
Sequencing a greater number of genes will identify more novel/rare variants whose clinical significance is uncertain. These include variants not seen before or identified in a small number of patients where the causal link to the disease is unproven. The clinical report will only include likely pathogenic mutations or variants where further investigation is recommended (for example by testing diabetic relatives to see if they have the same possible mutation). New clinical or genetic information may change the interpretation of pathogenicity. In accordance with best practice guidelines, known polymorphisms are not reported.
Please contact Kevin Colclough (kevin.colclough@nhs.net or 01392 408324).
