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

Transcription

1 Proposal form for the evaluation of a genetic test for NHS Service Gene Dossier Test Disease Population Triad Disease name and description (please provide any alternative names you wish listed) (A)-Testing Criteria OMIM number for disease # Gene name and description (please provide any alternative names you wish listed) OMIM number for Gene Severe combined Immunodeficiency with sensitivity to ionizing radiation (autosomal recessive) Alternative names SCID RS-SCID T - B - NK + SCID Athabascan-type severe combined immunodeficiency (SCIDA). SCIDs are a heterogeneous group of inherited disorders that arise from variety of molecular defects and deficits in both cell mediated and humoural immunity. The presentation is similar is in all defined conditions and characterised by profound abnormalities in T, B and NK cell development and function. Children present at 3-6 months with failure to thrive, recurrent infections and increased susceptibility to opportunistic infection. DCLRE1C (DNA cross link repair protein 1C) ARTEMIS SCIDA; SNM1C; A-SCID; RS-SCID; DCLREC1C; FLJ11360; FLJ36438 The Artemis gene is located at 10p and is involved in DNA repair during V(D)J recombination. It comprises of 18 exons and spans 56,665bp. Mutations in the Artemis gene are associated with T - B - NK+ SCID, the type of SCID caused by lack of Artemis activity is called radio-sensitive SCID (RS-SCID) and its inheritance pattern is autosomal recessive Mutational spectrum for which you test Technical Method (s) Validation Process 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 For how long have you been providing this service? Point mutations, small insertions & deletions Direct Sequence analysis (Long range PCR and MLPA to look for large rearrangements and dosage will be investigated) Sequencing is a standard analytical method used in the laboratory for a range of diagnostic services requiring mutation detected. The laboratory participates in external quality assurance for sequence analysis. No 1

2 Is there specialised local clinical/research expertise for this disease? Are you testing for other genes/diseases closely allied to this one? Please give details Your Activity How many tests do you (intend to) provide annually in your laboratory? Based on experience how many tests will be required nationally (UK)? Please identify the information on which this is based Yes No Please provide details The molecular immunology laboratory based in Great Ormond Street NHS Trust is experienced in the diagnosis of a variety of immunodeficiencies. We currently test for the following SCIDs: X-SCID, JAK3 SCID, IL7Ra SCID, and RAG SCID which is closely related to this disorder. ~20 ~20 this will include the number of T-B-NK+ SCIDs seen at GOSH/Newcastle without RAG gene defects, plus a number of SCIDs/CIDs with oligoclonality without RAG mutations. In addition referrals will be received form outside the UK. 2

3 Epidemiology Estimated prevalence of disease in the general UK population 1/100,000 This figure is based on the frequency of RAG SCID Please identify the information on which this is based Estimated gene frequency (Carrier frequency or allele frequency) Radiation sensitivity testing is undertaken on cultured skin fibroblasts. This serves a screening test for this group of immune deficiencies where the same mechanisms involved in DNA repair (hence sensitivity to ionising radiation) are used in the generation of immune cells. This is currently unknown but based on the above prevalence and autosomal inheritance, the expected gene frequency is around 1/158 Please identify the information on which this is based Estimated penetrance Please identify the information on which this is based 100% All patients with defined mutations have presented with SCID or combined immunodeficiency. Target Population The essential clinical or family history features defining the target population must be described. (C)-Testing Criteria Patients with T-B-NK+ SCID who have no mutations in either RAG1 or RAG2, and all patients with radiosensitivity and oligoclonality who have no mutations in RAG1 or RAG2. Estimated prevalence of disease in the target population Approximately 50% of T-B-NK+ SCID patients who have no mutations in either RAG1 or RAG2 Intended Use (Please use the questions in Annex A to inform your answers) Please tick the relevant clinical purpose of testing Diagnosis Treatment Prognosis & Management Presymptomatic testing Risk Assessment YES NO Test Characteristics 3

4 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. Direct sequencing has a high sensitivity in this laboratory. We use big dye chemistry, ABI analysers (3100, 3130XL, 3730) and analysis by eye / Mutation Surveyor software. We participate and perform successfully in EQA programmes for sequence analysis. If a number of genes will be tested, please include your testing strategy and data on the expected proportions of positive results for each part of the process. It may be helpful to include a diagram to illustrate the testing strategy. Clinical sensitivity and specificity of test in target population 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) The sensitivity is as yet unproven but is expected to be at least 90% for sequence analysis and a further 10% for dosage/rearrangements. The specificity is very high 4

5 Clinical validity (positive and negative predictive value in the target population) Given the clinical features and combined screening of RAG1/2, the positive predictive value will be high. 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). The denominator in this case is the number of people with a positive or a negative test respectively - not the number with or without the disease. The clinical validity may be calculated knowing the sensitivity and the specificity and the prevalence of the disease in the population being studied. Positive and negative predictive values depend critically on the prevalence of the disease in the test population 5

6 Clinical utility of test in target population (Please refer to Appendix A) Please provide a full description of the clinical care pathway for those individuals undergoing testing. This should include details of which medical specialties will be able to refer for testing. (B)-Testing Criteria How will the test add to the management of the patient or alter clinical outcome? The immunology of patients presenting with severe combined immunodeficiency (SCID) is evaluated by immunophenotyping, immunoglobulin measurements and functional assays in the immunology and haematology laboratory. Patients with T-B-SCID are referred to a NCG immunology centre (Great Ormond Street or Newcastle General) where they will undergo a Haematopoietic stem cell transplantation (HSCT). Patients with T-B-NK+ SCID will initially be screened for mutations in the RAG1 and RAG2 genes. If no mutation is identified then sequencing of DCLRE1C (Artemis) gene will be undertaken. Knowledge of the genetic defect will enable carrier and prenatal testing to be offered to affected families. For patients with atypical SCID, knowledge of a genetic defect would provide a diagnosis and result in HSCT for the patient. 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? Based on our experience with testing for other forms of SCID this test will enable prenatal diagnosis to be offered to affected families. It will also decrease the need for additional investigations and save resources as this test is currently offered in Paris for 2500 Euros. 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 Although immunophenotyping will identify a T-B-NK+ SCID, there is no test available to specifically identify Severe combined Immunodeficiency with sensitivity to ionizing radiation. Are there specific ethical, legal or social issues with this test? No Please complete the referral pathway diagram on the following page and the testing criteria form. 6

7 Referral Pathway Template NOTE: Please use this page as a template. Please expand the test boxes manually as needed. TARGET POPULATION (Description) T-B-NK AND SCID with no mutations in RAG1 & RAG2 AND radio sensitivity (on cultured skin fibroblasts) and oligoclonality with no mutations in RAG1 and RAG2. WHAT TYPE AND LEVEL OF PROFESSIONAL OR REFERRER DO YOU ACCEPT SAMPLES FROM? Paedatric Immunologists Clinical Geneticists PLEASE PROVIDE DETAILS OF HOW REFERRALS WILL BE ASSESSED FOR APPROPRIATENESS? By review with Immunology under the direction of a Consultant Paediatric Immunologist Nearly all cases of SCID have very low/absent numbers of T cells. Patients are then grouped into those who have B cells and those who don t. Further classification can then be made according to presence/absence of NK cells. A number of T - B - NK+ SCID patients have been shown to have mutations in RAG1/2. In some of those patients with no RAG1/2 mutations it has been shown that their fibroblasts are sensitive to ionizing radiation and that they are likely to have a defect in DNA double strand break repair. Several of these patients have been shown to have a mutation in the Artemis gene HOW MANY TESTS DO YOU EXPECT TO PERFORM ANNUALLY? 20 7

8 UKGTN Testing criteria: Name of Disease(s): SEVERE COMBINED IMMUNODEFICIENCY WITH SENSITIVITY TO IONIZING RADIATION (602450) Name of gene(s): DNA cross-link repair 1C (PSO2 homolog, S. cerevisiae); DCLRE1C (605988) 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 Paediatric Immunologists Tick if this refers to you. Minimum criteria required for testing to be appropriate as stated in the Gene Dossier: Criteria Family history of disease with identified mutation(s) OR T-B-NK+ AND SCID with no mutations in RAG1 and RAG2 AND Radio sensitivity (on cultured skin fibroblasts) and oligoclonality with no mutations in RAG1 and RAG2 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. 8