Introduction 1 2 3 4 5 GCK HNF1A 1 GCK HNF1A GCK Table 1 Genes in which mutations cause MODY   Gene symbol (other symbol) GCK HNF1A TCF1 HNF4A PDX1 IPF1 NEUROD1 HNF1B TCF2 Protein Glucokinase Hepatocyte nuclear factor-1 alpha Hepatocyte nuclear factor-4 alpha Insulin promoter factor-1 Neurogenic differentiation 1 Hepatocyte nuclear factor-1 beta Chromosome locus 7p13 12q24.31 20q13.12 13q12.2 2q31.3 17q12 Gene Accession no. NM_000162.2 NM_000545.4 a NM_000209.2 NM_002500.2 NM_000458.1 OMIM * (Gene) 138079 142410 600281 600733 601724 189907 OMIM # (Phenotype) 125851 600496 125850 606392 606394 137920 Mutation frequency (%) (not known in ~20% of cases) 20–50 20–50 ~5 <1 <1 ~5 HNF4A 45 46 HNF4A a HNF4A HNF4A GCK 1c 1c 6 7 GCK 8 HNF1A HNF4A HNF4A 9 10 HNF1A 11 12 GCK HNF1A HNF4A 13 14 HNF1A GCK 15 HNF1A HNF1A HNF1A(A) 16 17 PDX1 IPF1 18 19 NEUROD1 20 21 HNF1B 22 24 CEL 25 GCK HNF1A HNF4A Methods A group of European clinicians and scientists met on 22 May 2007 at a workshop to formulate best practice guidelines for molecular genetic testing in MODY. Discussions focused on clinical criteria for selection of patients for testing, methodologies, interpretation of results and reporting those results to the referring clinicians. A draft document was posted on 24 August 2007 and an online editing tool was used by participants to produce consensus guidelines. Results Clinical criteria for testing GCK GCK GCK 26 GCK GCK 27 1c 27 , GCK GCK 28 GCK GCK 29 Persistently raised fasting blood glucose in the range of 5.5–8 mmol/l before, during and after pregnancy. An increment of <4.6 mmol/l on at least one OGTT (either during or after pregnancy). A parent may have mild type 2 diabetes but often this has not been detected and so the absence of family history should not exclude the diagnosis. HNF1A HNF1A HNF1A Young-onset diabetes (typically before 25 years old in at least one family member). Non-insulin-dependent outside the normal honeymoon period (3 years), e.g. not developing ketoacidosis in the absence of insulin, good glycaemic control on less than the usual replacement dose of insulin, or detectable C-peptide measured when on insulin with glucose >8 mmol/l. 27 The absence of pancreatic islet autoantibodies. 11 9 30 Several features suggesting monogenic diabetes rather than a diagnosis of young-onset type 2 diabetes should be considered: no marked obesity or evidence of insulin resistance in diabetic family members, absence of acanthosis nigricans and whether the family is from an ethnic background with a low prevalence of type 2 diabetes (e.g. of European descent). HNF4A HNF4A 1 HNF1A 31 HNF4A HNF1A HNF1A 32 HNF4A 33 34 HNF4A HNF4A HNF4A 34 Children and young adults with diabetes and a strong family history of diabetes: testing for HNF1A mutations HNF4A Testing methodology http://ngrl.man.ac.uk/SNPCheck/index.html Interpretation of results  Reporting http://www.emqn.org http://www.cmgs.org http://www.ssgm.ch http://www.hgvs.org/mutnomen 1 35 http://www.blocks.fhcrc.org/sift/SIFT.html http://www.genetics.bwh.harvard.edu/pph http://www.fruitfly.org http://rulai.cshl.edu/cgi-bin/tools/ESE3/esefinder.cgi?process=home GCK HNF1A HNF1B 36 38 39 42 43 Polymorphisms Some laboratories include details of polymorphisms detected in the report. The reasons for doing this include: (1) making all data available to the requesting clinician based on the rationale that a polymorphism may later be reclassified as a mutation; and (2) identifying heterozygous SNPs excludes a gene deletion involving the exon(s) in question. However, this information can cause confusion or even misinterpretation of the result (A. T. Hattersley, unpublished data) and it certainly adds to the length of the report. While in some cases there may be reports in the literature of an association with type 2 diabetes or reduced insulin secretion, these polymorphisms do not cause MODY and we recommend that they should be excluded from the report. Treatment HNF1A/4A Other issues GCK HNF1A/HNF4A 44 Conclusions Molecular genetic testing is useful in patients with MODY because it confirms a diagnosis of monogenic diabetes, predicts likely clinical course, defines risk for relatives and determines treatment. At the present time, molecular genetic testing for MODY is relatively expensive and phenotypic selection prior to testing is normal practice. With the development of new technologies it is likely that these costs will decrease in time and that the analysis of genes associated with monogenic diabetes may become routine for all newly diagnosed patients. In the meantime we hope that these guidelines will be useful in determining which patients should be offered testing, and in the interpretation and reporting of the test results. Below is the link to the electronic supplementary material.
               				 ESM (PDF 12.9 kb)