Proposal form for the evaluation of a genetic test for NHS Service Gene Dossier/Additional Provider

Transcription

1 Proposal form for the evaluation of a genetic test for NHS Service Gene Dossier/Additional Provider TEST DISEASE/CONDITION POPULATION TRIAD Submitting laboratory: Cambridge RGC Approved: September Disease/condition approved name and symbol as published on the OMIM database (alternative names will be listed on the UKGTN website) 2. OMIM number for disease/condition Disease/condition please provide a brief description of the characteristics of the disease/condition and prognosis for affected individuals. Please provide this information in laymen s terms. HEMOCHROMATOSIS; HFE Hereditary haemochromatosis is a common genetic condition characterised by progressive iron loading and organ damage. Complications include cirrhosis, hepatocellular carcinoma, diabetes, cardiomyopathy, arthropathy and hypogonadism. The condition is entirely preventable if diagnosed early and iron removal by phlebotomy is instituted. 85% affected in the UK have two copies of the mutation C282Y or, less commonly, a combination of C282Y and a minor mutation H63D within the HFE gene. Therefore 15% of cases remain uncharacterized. Increasingly, cases have been described where there are additional causative mutations in the HFE gene. Full HFE sequencing has the potential to explain a significant proportion of unexplained cases and enable family screening. 4. Disease/condition mode of inheritance Autosomal recessive 5. Gene approved name(s) and symbol as Hemochromatosis, HFE (full sequencing) published on HUGO database (alternative names will be listed on the UKGTN website) 6. OMIM number for gene(s) Gene description(s) Chromosome 6p21.3, 7 exons, transcript length 1943 bps, 348 residues 7b. Number of amplicons to provide this 7 test 7c. MolU/Cyto band that this test is Band D 2012/13 assigned to GenUs Band E 2013/24 8. Mutational spectrum for which you test including details of known common mutations 9. Technical method(s) DNA sequencing 10. Validation process Please explain how this test has been validated for use in your laboratory Coding region and splice sites for all coding exons Common mutations: C282Y, H63D We have several patients with uncommon mutations in HFE (determined in other laboratories) to use for validation purposes. Current strategies and methodologies used for other UKGTN approved tests offered by this laboratory will be used to validate the test for service use. 11a. Are you providing this test already? No (only C282Y and H63D as standard) 11b. If yes, how many reports have you produced? N/A

2 11c. Number of reports mutation positive N/A 11d. Number of reports mutation negative N/A 12. For how long have you been providing this service? N/A 13a. Is there specialised local Yes clinical/research expertise for this disease? 13b. If yes, please provide details Prof TM Cox and Dr WJH Griffiths are international experts in this field 14. Are you testing for other Yes as well as the 2 common mutations in HFE, we genes/diseases/conditions closely allied to provide a unique UKGTN testing service for mutations this one? Please give details in HFE2A, HFE2B (juvenile haemochromatosis) and HFE4 (ferroportin disease) Your current activity Not applicable for full HFE sequencing If applicable - How many tests do you currently provide annually in your laboratory? 15a. Index cases 15b. Family members where mutation is known Your capacity if Gene Dossier approved 30 How many tests will you be able to provide annually in your laboratory if this gene dossier is approved and recommended for NHS funding? 16a. Index cases 15 16b. Family members where mutation is 15 known Based on experience how many tests will be required nationally (UK wide) per annum? 30 Workload of related genes HFE2 and HFE4 and published data on non-c282y HFE positive cases 17a. Index cases 15 17b. Family members where mutation is 15 known 18. National activity (England, Scotland, We will be able to provide a UK-wide service as for Wales & Northern Ireland) HFE2 and HFE4 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.

3 EPIDEMIOLOGY 19. Estimated prevalence of condition in the general UK population 20. Estimated gene frequency (Carrier frequency or allele frequency) 21. Estimated penetrance 22. Estimated prevalence of condition in the target population. The target population is the group of people that meet the minimum criteria as listed in the Testing Criteria. Prevalence of haemochromatosis 1/1000 Based on known homozygous frequency (1/200) and penetrance Frequency of non-c282y mutations rare (<1/1000) Published reports of non-c282y HFE mutations particularly centres which have screened for research purposes Biochemical (iron loading) penetrance 90% in males, 20% in females. Disease penetrance approximately 20%. Frank haemochromatosis 1%. Obtained from the published literature. 80% INTENDED USE 23. Please tick the relevant clinical purpose of testing Diagnosis X Yes No Treatment Yes X No Prognosis & management X Yes No Presymptomatic testing Yes X No Carrier testing for family members X Yes No Prenatal testing Yes X No

4 TEST CHARACTERISTICS 24. Analytical sensitivity and specificity This should be 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. Bi-directional sequencing coupled with Mutation Surveyor software has a quoted sensitivity of >99% and specificity of >99% 25. Clinical sensitivity and specificity of test in target population The clinical sensitivity of a test is the probability of a positive test result when condition 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 condition (for specificity). Comprehensive data not available. Specificity likely to be high if cases selected appropriately. 26. 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 condition or predisposition. It is measured by its positive predictive value (the probability of getting the condition given a positive test) and negative predictive value (the probability of not getting the condition given a negative test). The positive predictive value is likely to be high if used in biochemically and histopathologically affected individuals and their family members. The negative predictive value is likely to be high if used for screening family members 27. Testing pathway for tests where more than one gene is to be tested 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. Common mutations in HFE (C282Y and H63D) to be excluded prior to full HFE sequencing CLINICAL UTILITY 28. How will the test add to the management of the patient or alter clinical outcome? Securing a genetic diagnosis reinforces that iron loading and organ damage will continue unabated if the patient is not treated. At present many are classed as carriers for C282Y (and therefore thought not to have hereditary haemochromatosis). By finding additional causative mutations the diagnostic certainty of familial transmission is increased and treatment can be commenced immediately knowing that it is purposeful. Family members will benefit from a more informative screening process. 29. How will the availability of this test impact on patient and family life? Provide accurate diagnosis of the genetic nature of the patient s iron overload and reinforce the need for treatment. Untreated the condition can cause significant morbidity and mortality such as due to cirrhosis and liver cancer. The test can only improve patient well being and associated family well being. 30. Benefits of the test Please provide a summary of the overall benefits of this test. Provide accurate diagnosis of the genetic nature of the patient s iron overload and reinforce the need for treatment, preventing the complications of the disorder. 31. 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. A diagnosis of iron overload can be made without genetic tests. The genetic test reinforces that iron overload will continue both in the index case and in positive family members. There is no alternative if the patient is not homozygous for C282Y or has the compound heterozygous form C282Y/H63D 32. Please describe any specific ethical, legal or social issues with this particular test. Due to the high penetrance of the clinical phenotype and the greatly improved prognosis once the condition is identified, there are no specific ethical, legal or social issues. 33. The Testing Criteria must be completed where Testing Criteria are not already available. If Testing Criteria are available, do you agree with them Yes If No: Please propose alternative Testing Criteria AND please explain here the reasons for the changes.

5 34. Savings or investment per annum in the diagnostic pathway on national expected activity, cost of diagnostics avoided and cost of genetic test. Please show calculations. Testing for HFE2 and HFE4 could be avoided 35. List the diagnostic tests/procedures that would no longer be required with costs. N/A Costs and type of imaging procedures Costs and types of laboratory pathology tests (other than molecular/cyto genetic proposed in this gene dossier) Costs and types of physiological tests (e.g. ECG) Cost and types of other investigations/procedures (e.g. biopsy) Total cost tests/procedures no longer required 36. REAL LIFE CASE STUDY In collaboration with the clinical lead, describe a real case example to illustrate how the test would improve patient experience. A 40 yr man presented with cirrhosis and grade 4 iron. No known risk factors for liver disease. This fits the profile of hereditary haemochromatosis however he tested as a carrier for C282Y only and was negative for juvenile and ferroportin mutations. On full HFE sequencing performed in a separate laboratory (which took several months to arrange) was found to have the additional mutation C282F. This is predicted on in silico analysis to be more severe than C282Y. The phenotype seen here is more severe than is usually seen at this age with C282Y homozygosity and therefore now explained the patient does have genetic haemochromatosis. Family members are in the process of being screened. HFE sequencing would have been indicated from the outset so a diagnosis would have been expedited and HFE2/HFE4 sequencing not required. 37. For the case example, if there are cost savings, please provide these below: Savings from not having to test additional non-hfe genes such as HFE2 and HFE4 PRE GENETIC TEST Costs and type of imaging procedures Costs and type of laboratory pathology tests (other than molecular/cyto genetic proposed in this gene dossier) Costs and type of physiological tests (e.g. ECG) Cost and type of other investigations/procedures (e.g. biopsy) Cost outpatient consultations (genetics and non genetics) Total cost pre genetic test POST GENETIC TEST Costs and type of imaging procedures Costs and types laboratory pathology tests (other than molecular/cyto genetic proposed in this gene dossier) Cost of genetic test proposing in this gene dossier Costs and type of physiological tests (e.g. ECG) Cost and type of other investigations/procedures (e.g. biopsy) Cost outpatient consultations (genetics and non genetics) Total cost post genetic test 38. Estimated savings for case example described

6 UKGTN Testing Criteria Approved name and symbol of disease/condition(s): Hemochromatosis; HFE Approved name and symbol of gene(s): hemochromatosis; HFE (full HFE sequencing) OMIM number(s): OMIM number(s): Patient name: Patient postcode: Date of birth: NHS number: Name of referrer: Title/Position: Lab ID: Referrals will only be accepted from one of the following: Referrer Clinical Geneticists Consultant Hepatologist Tick if this refers to you. Minimum criteria required for testing to be appropriate as stated in the Gene Dossier: Criteria Raised transferrin saturation and serum ferritin AND Not C282Y/C282Y or C282Y/H63D Tick if this patient meets criteria 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