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: Birmingham 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 PLATELET DISORDER, FAMILIAL, WITH ASSOCIATED MYELOID MALIGNANCY; (FPD/AML) 3. 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. Individuals with pathogenic RUNX1 mutations have a congenital platelet disorder comprising both qualitative and quantitative platelet defects (such as thrombocytopenia) and are at increased risk of developing acute myeloid leukaemia. RUNX1 mutation carriers are also at risk of developing myelodysplastic syndrome and lymphoblastic leukaemia. The median incidence of associated myeloid malignancy in FPD/AML is 35%. Some individuals consider prophylactic stem-cell transplant to reduce their risk of developing AML. 4. Disease/condition mode of inheritance Autosomal dominant 5. Gene approved name(s) and symbol as published on HUGO database (alternative names will be listed on the UKGTN website) runt-related transcription factor 1; RUNX1 6. OMIM number for gene(s) Gene description(s) RUNX1 located at 21q22.12 encodes a transcription factor critical for normal haematopoiesis. RUNX1 (also known as CBFalpha) forms a heterodimer with CBFbeta and acts as a transcriptional organiser, recruiting other lineage-specific transcription factors to their promoters. RUNX1 is predominantly expressed in bone marrow, peripheral blood and the thymus. 7b. Number of amplicons to provide this test 7c. MolU/Cyto band that this test is assigned to 8. Mutational spectrum for which you test including details of known common mutations 6 D Point mutations including splice sites and small rearrangements. Most mutations are private. 9. Technical method(s) Sanger sequencing 10. Validation process Please explain how this test has been validated for use in your laboratory RUNX1 analysis was introduced into the laboratory incidentally. A patient with sporadic AML was shown to have acquired isodisomy of chromosome 21 (AID21), and it was postulated that RUNX1 located at 21q22 was a good candidate for loss of heterozygosity via doubling up of a somatic deleterious mutation. To

2 11a. Are you providing this test already? test this hypothesis, published primers (Dicker et al 2007) were used to screen cdna in four overlapping fragments via sequence analysis, and a missense mutation in exon 5, D171G, was found in an apparently homozygous state, consistent with AID21. The laboratory already had a positive control for a RUNX1 mutation in exon 4 thanks to a local family with FPD/AML. This family had been screened by a research lab who found the germline mutation, and WMRGL had been able to offer presymptomatic testing to at risk relatives using primers for exon 4 only. Knowing of a few other families with suspected familial AML, we decided to set-up RUNX1 screening as a diagnostic service, designing primers for genomic DNA which encompassed the splice sites, and choosing to screen exons 3-8 where all mutations reported to date have been sited. Sequence products from normal controls were checked for quality and identity confirmed against the reference sequence (NM_ ). Primers were all SNP checked using the Manchester NGRL website. Mutations (one splice-site, one frameshift) were found in two other families and segregated with the disease. Two individuals, both with confirmed AML (one from each family) had a second mutation, likely to be the somatic second hit, demonstrating the importance of confirming the germline nature of a RUNX1 mutation before offering presymptomatic testing, as somatic RUNX1 mutations are common in sporadic AML Nine other individuals/families with familial AML or suspected FPD/AML have been screened for RUNX1 mutations but none have been found. 11b. If yes, how many reports have you produced? 22 11c. Number of reports mutation positive 9 11d. Number of reports mutation negative For how long have you been providing this service? 2 years 13a. Is there specialised local clinical/research expertise for this disease? 13b. If yes, please provide details West Midlands Regional Clinical Genetics Service provided counselling to one of the first families found to have a RUNX1 mutation, and has since seen members of our two other families. The Haematology departments of both Birmingham Queen Elizabeth Hospital and Birmingham Children s Hospital have experience of caring for FPD/AML families.

3 14. Are you testing for other genes/diseases/conditions closely allied to this one? Please give details Your current activity If applicable - How many tests do you currently provide annually in your laboratory? 15a. Index cases 11 15b. Family members where mutation is 9 known Your capacity if Gene Dossier approved 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 16b. Family members where mutation is known Based on experience how many tests will be required nationally (UK wide) per annum? Please identify the information on which this is based 17a. Index cases 5 17b. Family members where mutation is 15 known 18. 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. We have an extensive cytogenetic and molecular haemato-oncology department which provides a specialist genetic service for all patients with haematological malignancy within the West Midlands region. With rare exception, most individuals are referred with acquired neoplasms. For patients with a family history of AML, we offer RUNX1 mutation analysis, and CEBPA mutation analysis. CEBPA mutations are associated with pure familial AML No more than known families worldwide (excluding our 3). 3 families from a population of 5.5 million in the West Midlands suggest the incidence is much higher than that reported. At least 30 families in the UK. For every family where we have found a mutation, we have screened 3 others where we have not. Potentially we could screen individuals from 120 suspected FPD/AML families, based on our figures, to find the 30 affected UK families. These will manifest over time very difficult to predict when. Able to provide full national need.

4 EPIDEMIOLOGY 19. Estimated prevalence of condition in the general UK population Please identify the information on which this is based 20. Estimated gene frequency (Carrier frequency or allele frequency) Please identify the information on which this is based At least 30 families in the UK (see above). Given the small size of modern families and clinical heterogeneity of FPD/AML, the diagnosis could easily be overlooked and prevalence be much higher. Unknown but for the reasons expressed above, many individuals with FPD/AML and germline RUNX1 mutations may be assumed to have sporadic acquired AML (phenocopies). 21. Estimated penetrance Please identify the information on which this is based 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. At least 35% for developing AML (Owen et al. Blood 2008, 112;12: ). A higher proportion of individuals with germline RUNX1 mutations will have platelet defects, but these may be mild. 25% based on our limited experience INTENDED USE 23. Please tick the relevant clinical purpose of testing Diagnosis Treatment Prognosis & management Presymptomatic testing Carrier testing for family members Prenatal testing

5 TEST CHARACTERISTICS 24. Analytical sensitivity and specificity 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. Sensitivity of sequencing is >99%. Specificity is sequencing is >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). Clinical sensitivity, for small coding region & splice site alterations, is >99%. This test will not detect large rearrangements & whole gene deletions which have been reported in 3 families to date. However we plan to introduce an MLPA kit containing RUNX1 to identify these mutations. Clinical specificity is >98%. There is a small chance of identifying somatically acquired RUNX1 mutations in individuals with undiagnosed myelodysplastic syndrome, and a reasonable chance of identifying somatically acquired RUNX1 mutations in individuals with confirmed AML. Care must be taken to ensure that any RUNX1 mutation reported as such is in fact germline. 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). FPD/AML is an autosomal dominant condition with complete penetrance (Heller P.G. Atlas Genet Cytogenet Oncol Haematol. July Identification of a pathogenic germline mutation confirms the diagnosis of FPD/AML. Positive predictive value is 35% for AML, >99% for platelet abnormalities. Negative predictive value is >99% for FPD/AML. 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. N/A CLINICAL UTILITY 28. How will the test add to the management of the patient or alter clinical outcome? Patients with confirmed FPD/AML will have regular haematological monitoring (at least annually) to look for early changes in their bone marrow. They should also be sent for cytogenetic analysis and FLT3-itd mutation analysis (and other genetic tests where available e.g. NPM1) as this can also identify onset of acute leukaemia. If MDS or AML is diagnosed, they will receive appropriate treatment based on chemotherapy, or potentially a haematopoietic stem cell transplant. Stem cell transplants often make use of a related donor, and it is vital to ensure that potential donors do not carry the familial RUNX1 mutation to avoid a high risk of disease recurrence post-transplant (this scenario has previously been reported in RUNX1 families, see Owen et al. Blood 2008, 112;12: ). Furthermore, known RUNX1 gene mutation carriers can discuss the potential role of bone marrow harvest so that autologous bone marrow transplant remains a potential future therapeutic option. RUNX1 mutation analysis is the only means of diagnosing FPD/AML.

6 29. How will the availability of this test impact on patient and family life? Once diagnosis is confirmed, choice of therapy may be altered; for example a stem cell transplant in first remission may be considered. Patients will receive life-long regular cancer surveillance screening. At risk relatives who have confirmatory / presymptomatic RUNX1 analysis can enter a regular screening programme. There is no established care pathway because of the rarity of FPD/AML, and no professional guidelines to our knowledge. Recommendations for management of FPD/AML patients are lacking due to the low frequency of this disorder and need to be assessed individually. ( The above paragraph represents how the families in our region have been managed. There may be couples who wish to consider prenatal diagnosis, pre-implantation diagnosis or saviour sibling marrow transplantation that would require molecular confirmation of RUNX1 status. 30. Benefits of the test Please provide a summary of the overall benefits of this test. AML is a rare disease but most cases are sporadic, and very few familial. If a germline RUNX1 mutation is identified, and a diagnosis of FPD/AML is established, then both the proband and affected family members can undergo regular haematological screening for early detection of myeloid neoplasm. Some individuals even consider prophylactic stem-cell transplant to reduce their chance of developing AML. RUNX1 screening is important for donor selection to exclude potential related donors with the same leukaemogenic mutation. 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. No 32. Please describe any specific ethical, legal or social issues with this particular test. TESTING OF CHILDREN Onset of AML can occur in childhood and therefore testing of minors may be requested (in one of our RUNX1 families, one girl died of AML at the age of four). This brings about issues of removal of autonomy and the child s right not to know that they are a gene carrier. On the other hand, without the test, the chance to detect malignancy early may be lost as children may not be under regular surveillance. Furthermore in known gene carriers, there may be a case for harvesting and storing bone marrow for a potential autologous transplant, if this were to be the most appropriate or only future potential treatment option, despite the uncertainties in light of the individual s genetic status. Exclusion of a RUNX1 mutation can significantly reduce parental anxiety and in some instance avoid unnecessary doctor s appointments or investigations for co-incidental clinical findings such as bruising. PRENATAL Requests for prenatal analysis for FPD, a disorder with potentially a penetrance figure as low as 35% for development of malignancy, present an ethical dilemma. Around half of patients who develop AML before the age of 60 can be cured (prognosis much worse for older patients), but with an inherited predisposition there is always the chance that a second malignancy could develop.

7 Parents may also request prenatal analysis in their desire to create a saviour sibling who can act as a stem-cell donor for a child diagnosed with AML. 33. The Testing Criteria must be completed where Testing Criteria are not already available. If Testing Criteria are available, do you agree with them /No If No: Please propose alternative Testing Criteria AND please explain here the reasons for the changes. See below 34. Savings or investment per annum in the diagnostic pathway based on national expected activity, cost of diagnostics avoided and cost of genetic test. Please show calculations. RUNX1 mutation analysis costs 282 for a full screen, 129 for a confirmatory/presymptomatic test. 20 tests per year would cost ( 282x5)+( 129x15)= 3345 RUNX1 mutation analysis is the only means of diagnosing FPD/AML. The benefit is an early diagnosis and reduction in anxiety for family members. 35. List the diagnostic tests/procedures that would no longer be required with costs. We are not aware of any routine surveillance programmes for family members at risk of FPD/AML, other than for confirmed mutation carriers. However it is possible that some relatives may be anxious about the potential for developing AML if they have a strong family history, and they may present to their GP or clinic more often with symptoms such as tiredness and bruising. The availability of a definitive test for those patients testing negative for the familial mutation should alleviate anxiety and prevent additional clinic appointments. It is very difficult to predict how often the above situation occurs and to quantify the costs but it is well documented that patient anxiety will potentially increase the rate of seeking medical advice. 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. Patient X presented to the Clinical Genetics department with a borderline low platelet count requesting presymptomatic testing for the RUNX1 mutation previous found by a research laboratory in an affected sister. The sister died of leukaemia aged 32, and her daughter died of MDS aged just 4. The familial RUNX1 G138EfsX10 frameshift mutation was detected in patient X, who on the basis of this result is now monitored by a specialist haemato-oncology team and future therapeutic options, including storage of stem cells and the option of prophylactic stem-cell transplant, considered. Patient X had a child, Y, who at the age of nine underwent presymptomatic testing, precipitated by the family anxiety from perceived easy bruising. He was found not to have inherited the familial RUNX1 mutation, and was therefore not at risk of developing FPD/AML. In addition to the reduction in anxiety, patient Y did not need to undergo any additional investigation or surveillance for onset of leukaemia.

8 37. For the case example, if there are cost savings, please provide these below: No cost savings for the two examples provided PRE GENETIC TEST Costs and type of imaging procedures Costs and type of laboratory pathology tests : Full blood counts (annual) (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): Bone marrow Biopsy but dependent on other findings whether required Cost outpatient consultations (genetics and non genetics) Annual Haematology outpatients Clinical genetics outpatients 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) Possible stem cell transplant Stem cell storage Cost outpatient consultations (genetics and non genetics) Positive results: Monitoring by haematology outpatient consultant Clinical Genetics outpatient appointments for family members Negative results: Important group removed from screening and testing Total cost post genetic test 38. Estimated savings for case example described

9 UKGTN Testing Criteria Approved name and symbol of disease/condition(s): Platelet Disorder, Familial, with Associated Myeloid Malignancy; FPD/AML Approved name and symbol of gene(s): runt-related transcription factor 1; RUNX1 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 Consultant Clinical Geneticist Consultant Haematologist Tick if this refers to you. Minimum criteria required for testing to be appropriate as stated in the Gene Dossier: Criteria Proband with MDS/AML/platelet abnormality AND family history of MDS/AML/ALL (at least one first or second degree relative) At risk family members where familial mutation is known 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