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 Leber congenital amaurosis OMIM number for disease Disease alternative names please provide any alternative names you wish listed Early onset retinal dystrophy Disease please provide a brief description of the disease characteristics Disease - mode of inheritance Gene name(s) OMIM number for gene(s) Gene alternative names please provide any alternative names you wish listed Gene description(s) (including number of amplicons). Mutational spectrum for which you test including details of known common mutations 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? Leber Congenital Amaurosis 2 Autosomal Recessive Retinitis Pigmentosa Defects in RPE65 cause LCA which is a clinically and genetically heterogeneous group of early-onset and severe retinal degenerations, generally inherited in an autosomal recessive manner. Affected infants have little or no retinal photoreceptor function as tested by electroretinography. LCA represents the most common genetic cause of congenital visual impairment in infants and children. Defects in RPE65 also cause retinitis pigmentosa. RP leads to degeneration of retinal photoreceptor cells. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. Autosomal Recessive RPE65 RETINAL PIGMENT EPITHELIUM-SPECIFIC PROTEIN, 65-KD Retinitis Pigmentosa 20 (RP20) RPE65 has 14 encoding exons across 21136bp of genomic DNA and encodes 533 amino acids. This gene is amplified in 10 amplicons (UKGTN MOLU Band D). The screen detects point mutations and small insertion deletions. The c.1102t>c [p.tyr368his] mutation accounts for 28% of the mutations we have found so far. Bi-directional fluorescent sequencing for point mutations and indels. We have screened 47 patients for the RPE65 gene finding the disease causing mutations in 6 individuals. All mutations found were confirmed with two fresh dilutions. We also tested 8 individuals who had both disease causing mutations previously identified in a research setting. We confirmed both mutation in all 8 individuals Yes Number of reports issued: 57 Number of reports mutation positive: 16 Number of reports mutation negative: 41 1 year 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 Current Activity If applicable - How many tests do you currently provide annually in your laboratory? 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? Based on experience how many tests will be required nationally (UK wide)? 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. Yes No Please provide details Close links are retained with the Regional Clinical Genetics Service, Manchester Royal Eye Hospital and Moorfields Eye Hospital. We currently offer testing for a wide range of ophthalmic genetic disorders. X-linked and dominant retinitis pigmentosa (gene dossiers accepted), choroideremia, macular dystrophy, Best disease (gene dossiers pending). Samples tested so far: 8 research confirmations 47 complete RPE65 gene screens 2 Reflex tests (mutations known in family) We would expect this to rise if this test is approved for NHS funding. We anticipate a workload of up to 60 index cases pa and a further 10 reflex tests. We can meet this capacity in house. We anticipate the above activity would meet the National demand. We are the only laboratory offering this service in the UK. 2

3 Epidemiology Estimated prevalence of disease in the general UK population Estimated gene frequency (Carrier frequency or allele frequency) Estimated penetrance Target Population Description of the population to which this test will apply (i.e. description of the population as defined by the minimum criteria listed in the testing criteria) Estimated prevalence of disease in the target population The prevalence of LCA is between 1/30,000 (Koenekoop, 2004) and 1/81,000 (Stone, 2007), and it accounts for 5% of all inherited Retinopathies (Koenekoop, 2004). Koenekoop, Survey Of Ophthalmology Volume 49,Number 4, July August 2004 Stone, Lxiv Edward Jackson Memorial Lecture,American Journal Of Ophthalmology 2007 LCA is a heterogeneous disorder (>11 loci described to date) therefore accurate estimates of gene frequency are not possible. Mutations in RPE65 are estimated to account for approx. 6% of familial LCA (den Hollander 2008) Den Hollander et al,progress in Retinal and Eye Research 27 (2008) All pathogenic variants described to date, when present in homozygous or compound heterozygous form, have been fully penetrant. The target population is defined by the LCA phenotype, i.e. only cases with a high index of suspicion (ascertained by clinical geneticists or collaborating ophthalmologists) and a high probability of carrying a RPE65 mutation are offered testing. Reflex testing (carrier and predictive) will be made available to family members. Testing will be offered to patients with severe visual impairment usually before age 2 years AND Extinguished or severely reduced scotopic and photopic electroretinogram (ERG) AND In older children, night vision blindness followed by loss of midperipheral visual field. The test will be available to all UK inhabitants. Only individuals with a high prior likelihood of carrying a mutation (i.e. affected) will be tested. In the first year of screening we identified causative mutations in 6/47 (12%). Intended Use (Please use the questions in Annex A to inform your answers) Please tick the relevant clinical purpose of testing YES NO Diagnosis Treatment Prognosis & Management Presymptomatic testing Risk Assessment for family members Risk Assessment prenatal testing 3

4 Test Characteristics 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. 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) 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). On the basis of re-sequencing of positive controls we estimate that the analytical sensitivity and specificity of the technique used (Sanger sequencing) will be greater than 98%. This test has a relatively low clinical sensitivity due to the heterogeneity of the disorder. Referrals are predominantly from geneticists and paediatric ophthalmologists in Manchester and Moorfields Eye Hospitals as well as by members of the Eye Genetics Group (EGG). In our test validation cohort a pathogenic variant has been found in 12% of patients with a clinical suspicion of LCA or ARRP. We would expect that unaffected patients would not have (two) mutations in RPE65 (although we have no data to support this). Given the high penetrance of RPE65 mutations, if pathogenicity can be proven the clinical validity of the test is ~100%. However missense changes account for approximately 65% of mutations. The clinical relevance of all variants is assessed according to current agreed practice. Most variants are predicted pathogenic due to their nature (frameshift, nonsense, splice site). A number of the missense changes seen in RPE65 are well characterised such as p.tyr368his, however a number of variants remain currently unclassified. Unclassified variants may be counted as potential false positive results. However for known pathogenic changes the negative predictive value will be approaching 100% 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. This is a single gene test 4

5 Clinical utility of test in target population (Please refer to Appendix A) Please provide a description of the clinical care pathway. How will the test add to the management of the patient or alter clinical outcome? 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. What are the consequences of not doing this genetic test. Commissioners have asked for specific information to support introduction of tests. Utility of test in the NHS In a couple of sentences explain the utility of this test for the disease(s) Leber congenital Amaurosis is the most severe of the inherited retinal degenerations. Highly genetically heterogeneous; it is known to be inherited in an autosomal recessive fashion in the majority of cases. RPE65 mutations account for ~10% of all LCA. Children diagnosed with retinal dystrophy under the age of 5 (early-onset severe retinal dystrophy, EOSRD) are seen by clinical geneticists and paediatric ophthalmologists. Genetic testing for early onset severe retinal disease (EOSRD) will have two immediate benefits. For parents of affected children it will offer the potential for prenatal diagnosis in future pregnancies. Counselling of families with LCA Positive genetic testing for EOSRD offers the potential for prenatal diagnosis in future pregnancies: we already have experience that some families may wish to access such services. In families with a high degree of consanguinity such testing offers the potential to develop carrier testing for unaffected adults. Leber Congenital Amaurosis is associated with severe early onset visual disability and blindness secondary to retinal degeneration. The condition is therefore associated with a significant and progressive disability in the context of normal general health that is also progressive. The condition is recessive in 99% of cases although dominant forms are known. Genetic counselling: Genetic testing for RPE65 mutations will provide a precise molecular diagnosis in ~10% of cases of LCA. This provides clearer information regarding carrier status and hence will provide choices (eg PND) that would not otherwise be available. Denying this testing will severely limit the reproductive choices of a significant number of patients. Carrier testing and prenatal diagnosis are currently not available through NHS mechanisms. This test identifies a very severe inherited retinal dystrophy and distinguishes this from identical phenotypes caused by mutations in other genes. First-trimester prenatal diagnosis is made possible. 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 Please describe any specific ethical, legal or social issues with this particular test? There is no alternative means of identifying RPE65-mediated LCA None known 5

6 UKGTN Testing criteria Name of Disease(s): LEBER CONGENITAL AMAUROSIS 1; LCA1 (204000) Name of gene(s): retinal pigment epithelium-specific protein 65kDa; RPE65 (180069) 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 Ophthalmologist Tick if this refers to you. Minimum criteria required for testing to be appropriate as stated in the Gene Dossier: Criteria Severe visual impairment usually before age 2 years AND Extinguished or severely reduced scotopic and photopic electroretinogram (ERG) AND In older children, night vision blindness followed by loss of midperipheral visual field. 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. 6