A new test for all MODY genes

The cost of this test is centrally funded by NHS England for NHSE patients meeting eligibility criteria (see Guidelines for Genetic Testing in MODY // Diabetes Genes). This test for 54 monogenic diabetes genes costs £650 for NHS referrals outside of England and £813 (£650 plus a 25% surcharge) for non-NHS referrals. 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 appropriateness of the referral and the best testing strategy for your patient (kevin.colclough@nhs.net or 01392 408324).

Venous blood in plastic EDTA bottles (minimum 5ml adults; 3ml children; 1ml neonates) or genomic DNA (minimum of 5µg).

The national target is 84 calendar days.

Potentially, yes. The test includes the LMNA gene in which pathogenic variants 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 pathogenic variants causing other phenotypes have been identified. Therefore the likelihood of finding a pathogenic variant that predisposes to, for example, dilated cardiomyopathy is low.  For patients with a clinical suspicion of a monogenic form of lipodystrophy, we sequence a panel of genes that includes FBN1.  Pathogenic variants in this gene cause Marfan syndrome (MFS) but a subset of variants occurring within the penultimate exon 64 result in a recently recognised syndrome consisting of partial manifestations of Marfan syndrome, a progeroid facial appearance, and clinical features of lipodystrophy (Passarge et al 2016 PMID: 26860060, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4989216/). Analysis of the FBN1 gene will be limited to detecting only known pathogenic variants in exon 64 causing Marfanoid–progeroid–lipodystrophy syndrome to avoid identifying a variant associated with classic MFS.

The test includes genes such as WFS1, HNF1B, GATA6 and the mitochondrial DNA variant m.3243A>G where diabetes occurs as part of a syndromic disorder.  The clinical expressivity and penetrance of the extra-pancreatic features are highly variable in these syndromes, and diabetes can be the only presenting feature at the time of testing for monogenic diabetes.  This test can therefore potentially result in an unexpected diagnosis of a syndromic disorder (Colclough et al 2022 PMID: 34789499). In these scenarios we will contact the referring clinician to discuss the clinical significance of this result for the patient and their family, and whether referral to a clinical genetics service is required, prior to issuing the formal report.

The test includes the ABCC8 and KCNJ11 genes since pathogenic activating variants cause sulphonylurea responsive diabetes. Congenital hyperinsulinism results from recessive inactivating ABCC8 and KCNJ11 variants; carrier status for hyperinsulinism (identification of a heterozygous inactivating variant) will not be reported. 

The test also includes a number of genes that cause recessively inherited forms of monogenic diabetes.  It is therefore possible that heterozygous carriers of pathogenic variants in these genes will be identified.  These heterozygous variants will not be disease-causing in these individuals and their carrier status will not be reported.

This test will identify the same types of pathogenic variants 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 variants located outside of the conserved splice site sequences 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. Pathogenic variants 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 variants or variants of uncertain significance 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 benign variants of no clinical significance are not reported.

Technical information can be found here.