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Proposal form for the evaluation of a genetic test for NHS Service Gene Dossier Test – Disease – Population Triad Disease – name Congenital Glucose-Galactose Malabsorption OMIM number for disease 606824 Disease – alternative names please provide any alternative names you wish listed MONOSACCHARIDE MALABSORPTION; GM Disease – please provide a brief description of the disease characteristics Glucose-Galactose Malabsorption presents within the first weeks of life with severe watery and acidic diarrhoea and dehydration. The disorder can be fatal within a few weeks unless glucose and galactose are eliminated from the diet. Patients may also present with neonatal or early onset diabetes. Disease - mode of inheritance Autosomal recessive Gene – name(s) SLC5A1 OMIM number for gene(s) 182380 SOLUTE CARRIER FAMILY 5 (SODIUM/GLUCOSE COTRANSPORTER), MEMBER 1 SODIUM-GLUCOSE TRANSPORTER 1; SGLT1 SODIUM-GLUCOSE COTRANSPORTER, INTESTINAL NA+/GLUCOSE COTRANSPORTER, HIGH AFFINITY; NAGT Gene – description(s) (including Located on 22q13.1; size: 71.39Kb; 15 coding exons (15 amplicons). number of amplicons). Gene – alternative names please provide any alternative names you wish listed Mutational spectrum for which you Missense, nonsense, test including details of known mutations. common mutations. splicing and small insertion/deletion Technical Method (s) Sequencing of the entire coding region and conserved splice sites. Validation Process Sequence analysis of the coding region and splice sites has been carried out for 1 patient. Sequence analysis for the identification of heterozygous and homozygous mutations is employed for screening of >30 genes in the laboratory. Note: please explain how this test has been validated for use in your laboratory Are you providing this test already? If yes, how many reports have you produced? Please give the number of mutation positive/negative samples you have reported Yes If Yes: Number of reports issued: 1 Number of reports mutation positive: 1 Number of reports mutation negative: 1 Approval Date: Sept 2010 Submitting laboratory: Exeter Molecular Genetics Copyright UKGTN © 2010 For how long have you been providing this service? Since February 2010 Is there specialised local clinical/research expertise for this disease? Yes Are you testing for other genes/diseases closely allied to this one? Please give details No Please provide details Genetics of diabetes research group led by Prof. Andrew Hattersley. Yes. Testing is offered for monogenic forms of diabetes and hyperinsulinism. Index cases: N/A Your Current Activity If applicable - How many tests do you Family members where mutation is known: N/A currently provide annually in your laboratory? Your Capacity if Gene Dossier Index cases: unlimited approved Family members where mutation is known: unlimited How many tests will you be able to provide annually in your laboratory if this gene dossier is approved and recommended for NHS funding? Based on experience how many Index cases: <5 tests. Population studies in the UK have not been tests will be required nationally (UK carried out. wide)? Family members where mutation is known: <5 tests. Please identify the information on which this is based Unknown National Activity (England, Scotland, Wales & Northern Ireland) If your laboratory is unable to provide the full national need please could you provide information on how the national requirement may be met. For example, are you aware of any other labs (UKGTN members or otherwise) offering this test to NHS patients on a local area basis only? This question has been included In order to gauge if there could be any issues in equity of access for NHS patients. It is appreciated that some laboratories may not be able to answer this question. If this is the case please write “unknown”. 2 Approval Date: Sept 2010 Submitting laboratory: Exeter Molecular Genetics Copyright UKGTN © 2010 Epidemiology Estimated prevalence of disease in the general UK population Rare- approximately 200 cases worldwide (Wright, Am J Physiol 1998, 275: 879-882). Accurate data is not available for the UK. Please identify the information on which this is based Estimated gene frequency (Carrier frequency or allele frequency) Unknown. Please identify the information on which this is based Estimated penetrance Please identify the information on which this is based 100% penetrance in 26 families studied (Martin et al, Nat Genet 1996, 12: 216-220) Mutations have been identified in British, French, Dutch, Belgium, African, Hispanic and Japanese families. Test will be used for all affected individuals with a clinical diagnosis of suspected Description of the population to which glucose/galactose malabsorption presenting in the neonatal this test will apply (i.e. description of period or early onset of neonatal diabetes and carrier testing the population as defined by the offered to relatives. minimum criteria listed in the testing criteria) Target Population Estimated prevalence of disease in the target population Unknown. Intended Use (Please use the questions in Annex A to inform your answers) Please tick the relevant clinical purpose of testing YES Diagnosis Treatment Prognosis & Management NO Presymptomatic testing Risk Assessment for family members Risk Assessment – prenatal testing 3 Approval Date: Sept 2010 Submitting laboratory: Exeter Molecular Genetics Copyright UKGTN © 2010 Test Characteristics An a lytic a l s e n s itivity a n d s p e c ificity This should be based on your own laboratory data for the specific test being applied for or the analytical sensitivity and specificity of the method/technique to be used in the case of a test yet to be set up. Single direction sequence analysis using Mutation Surveyor software - sensitivity 99% and specificity 99% (in-house data). Clinical sensitivity and specificity of test in target population Martin et al (1996) analysed the SLC5A1 gene in 30 affected individuals from 26 families. Homozygous mutations were identified in 16 families, 7 families were compound heterozygote and in 3 families only one mutation was detected. Mutations identified include missense, nonsense, frameshift and splicing. Mutations were shown to affect conformation of the sodium/glucose transporter affecting either trafficking to the plasma membrane or its function as a cotransporter. (Martin et al, Nat Genet 1996, 12: 216-220) The clinical sensitivity of a test is the probability of a positive test result when disease is known to be present; the clinical specificity is the probability of a negative test result when disease is known to be absent. The denominator in this case is the number with the disease (for sensitivity) or the number without disease (for specificity) Clinical validity (positive and negative predictive value in the target population) The clinical validity of a genetic test is a measure of how well the test predicts the presence or absence of the phenotype, clinical disease or predisposition. It is measured by its positive predictive value (the probability of getting the disease given a positive test) and negative predictive value (the probability of not getting the disease given a negative test). Glucose-Galactose Malabsorption produces a clinical picture similar to that of intestinal disaccharidase deficiency (Congenital Sucrase-Isomaltase Deficiency, OMIN 222900) caused by mutations in the Sucrase-Isomaltase gene. However the median age at the onset of watery diarrhea is later at 3 weeks (range, 2 to 16 weeks) and that the diarrhoea can persist for many months (Newton et al, J Pediat 1996, 128: 753-756). Testing pathway Please include your testing strategy if more than one gene will be tested and data on the expected proportions of positive results for each part of the process. Please illustrate this with a flow diagram. This can be added to the document as a separate sheet if necessary. 4 Approval Date: Sept 2010 Submitting laboratory: Exeter Molecular Genetics Copyright UKGTN © 2010 Clinical utility of test in target population (Please refer to Appendix A) Molecular analysis of the SLC5A1 gene in individuals with a clinical diagnosis of Congenital Glucose-Galactose Malabsorption will allow a definitive diagnosis. A molecular diagnosis will then provide means by which carrier testing can be offered to relatives and offspring at risk. Prenatal testing can be offered once the Please provide a description of the molecular diagnosis is confirmed. Those affected with the disorder clinical care pathway. can then be given appropriate treatment. How will the test add to the management of the patient or alter clinical outcome? Identifying affected patients who are SLC5A1 gene mutation carriers will allow treatment to be started immediately. Treatment involves complete elimination of glucose and galactose from the diet. Fructose and xylose are absorbed normally so fructose based formula are well tolerated by patients and leads to a dramatic improvement. Children thrive on fructose replacement formulas but symptoms return even in adulthood with as little as 6g of glucose. What impact will this test have on the NHS i.e. by removing the need for alternative management and/or investigations for this clinical population? Please provide evidence from your own service. Definitive diagnosis allows appropriate treatment of the affected individuals and will allow treatment to be started sooner, potentially avoiding the patient being cared for in a neonatal unit. What are the consequences of not doing this genetic test. Commissioners have asked for specific information to support introduction of tests. Potential fatal diarrhoea and dehydration in patients and affected siblings. Utility of test in the NHS In a couple of sentences explain the utility of this test for the disease(s) Molecular analysis of the SLC5A1 gene in individuals with a clinical diagnosis of Congenital Glucose-Galactose Malabsorption will allow a definitive diagnosis and allow appropriate treatment to be given. Is there an alternative means of diagnosis or prediction that does not involve molecular diagnosis? If so (and in particular if there is a biochemical test) please state the added advantage of the molecular test Diagnosis of Glucose-Galactose Malabsorption can be made by H 2 breath test (oral administration of glucose or galactose results in breath H 2 elevation greatly above 20 parts/million). The patient is given a small amount of pure lactose (typically 2g/kg), and breath readings are taken every 15, 30 or 60 minutes for two to three hours. Test is performed in duplicate. A molecular test will be quicker and easier to perform and will allow carrier testing for other family members. Please describe any specific ethical, legal or social issues with this particular test? Not applicable 5 Approval Date: Sept 2010 Submitting laboratory: Exeter Molecular Genetics Copyright UKGTN © 2010 UKGTN Testing criteria Name of Disease(s): GLUCOSE/GALACTOSE MALABSORPTION; GGM (606824) Name of gene(s): solute carrier family 5 (sodium/glucose cotransporter), member 1; SLC5A1 (182380) Patient name: Date of birth: Patient postcode: NHS number: Name of referrer: Title/Position: Lab ID: Referrals will only be accepted from one of the following: Referrer Consultant Clinical Geneticist Consultant Paediatrician/ Consultant Neonatologist Tick if this refers to you. Minimum criteria required for testing to be appropriate as stated in the Gene Dossier: Criteria Tick if this patient meets criteria Clinical diagnosis of Congenital Glucose-Galactose Malabsorption presenting in the neonatal period AND Family history strongly suggestive for recessive inheritance OR Family members of affected individuals with a known mutation in a primary or secondary degree relative If the sample does not fulfil the clinical criteria or you are not one of the specified types of referrer and you still feel that testing should be performed please contact the laboratory to discuss testing of the sample. 6 Approval Date: Sept 2010 Submitting laboratory: Exeter Molecular Genetics Copyright UKGTN © 2010