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

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1 Proposal form for the evaluation of a genetic test for NHS Service Gene Dossier Test Disease Population Triad Disease name Alagille syndrome 2 OMIM number for disease Disease alternative names please provide any alternative names you wish listed Disease please provide a brief description of the disease characteristics Disease - mode of inheritance Gene name(s) Alagille syndrome (ALGS) is a multisystem disorder primarily affecting the liver, heart, skeleton, eye and face. Diagnostic criteria proposed by Alagille et al (1987 Journal of Paediatrics Feb;110(2): ) combine the presence of bile duct paucity on liver biopsy with 3 of 5 major clinical features. These features include cholestasis, heart defects, vertebral abnormalities, ocular abnormalities and characteristic facial features. Since the introduction of genetic testing it is now widely recognised that there is highly variable expressivity in patients with Alagille syndrome. Many individuals present with milder clinical features and may only have 1 or 2 of the above systems affected (Kamath et al 2003, J Med Genet ). Invasive liver biopsies are now rarely performed. Autosomal dominant NOTCH2 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) NOTCH2; location 1p13, 34 coding exons (38 amplicons) Missense, nonsense, splicing and small insertion/deletion mutations. Sequencing of exons 1-34 and conserved splice sites. Validation Process Note: please explain how this test has been validated for use in your laboratory NOTCH2 sequence analysis was carried out using DNA from a patient with a diagnosis of Alagille syndrome and a JAG1 mutation. 1

2 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. No reports issued to date. For how long have you been providing this service? Is there specialised local clinical/research expertise for this disease? No Please provide details Are you testing for other genes/diseases closely allied to this one? Please give details Your Activity If applicable - How many tests do you currently provide annually in your laboratory? Your Activity 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)? Yes, Alagille syndrome type 1 (JAG1 gene) Index cases: Family members where mutation is known: Index cases: As required Family members where mutation is known: As required Index cases: <5 tests. Family members where mutation is known: <5 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. Not applicable 2

3 Epidemiology Estimated prevalence of disease in the general UK population The estimated prevalence of Alagille syndrome is 1;70,000 live births, although evidence suggests that this is an underestimate (Li et al. Nature Genetics. 1997;16: ) Estimated gene frequency (Carrier frequency or allele frequency) Unknown 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) Testing of 3 affected family members identified the familial mutation in all individuals. Mutation testing has not been carried out for unaffected family members (McDaniell et al. Am. J. of Hum. Genet. 2006;79: ). Individuals with a suspected diagnosis of Alagille syndrome who do not have a mutation in the JAG1 gene. Family members of individuals with an identified NOTCH2 mutation. Penetrance data is not available so testing may be requested on both affected and unaffected family members. 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 Diagnosis Treatment Prognosis & Management Presymptomatic testing Risk Assessment for family members Risk Assessment prenatal testing YES NO 3

4 Test Characteristics Analytical sensitivity and specificity Single direction sequence analysis using Mutation Surveyor software. Sensitivity 99% and specificity 99% (in-house data) 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. If more than one gene will be tested, please include your testing strategy and data on the expected proportions of positive results for each part of the process. Please illustrate this with a flow diagram. 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) Between 57 and 94% of patients with a clinical diagnosis of Alagille syndrome have a mutation in the JAG1 gene, suggesting that mutations in other genes, such as NOTCH2, may play a role in the Alagille syndrome phenotype. Limited data is available for the frequency of mutations in NOTCH2. One study has been reported, this study found that 2/11 probands with a clinical diagnosis of Alagille syndrome (both probands had 3/5 systems affected) and no JAG1 mutation had a mutation in NOTCH2 (McDaniell et al 2006 Am J Hum Genet vol. 79; ). Laboratory has not provided their own data for alagille jag1-ve samples 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). Alagille syndrome type 1 (JAG1 gene) shows a very variable phenotype. The presence of a mutation does not predict the likely severity of the phenotype. This is also likely to be true for Alagille syndrome type 2 as the affected mother and grandmother of proband 2 (from study above) had only renal disease and facial features. Both of the mutations identified are predicted to be pathogenic. The mutation in proband 1 (c g>a) showed an abnormally spliced product on gel electrophoresis and cdna sequencing. The mutation in proband 2 (p.c444y) segregated with disease in all 3 affected family members, was not present in unaffected family members and affected a cysteine residue within a functionally important EGF repeat. 4

5 Clinical utility of test in target population (Please refer to Appendix A) Please provide a description of the clinical care pathway. Molecular analysis of the NOTCH2 gene in individuals with a clinical diagnosis of Alagille syndrome will allow a definitive diagnosis. A molecular diagnosis will then provide means by which testing can be offered to relatives and offspring at risk. Identification of a pathogenic mutation will allow the option of prenatal diagnosis. Studies are limited but Alagille syndrome 2 appears to be indistinguishable from Alagille syndrome 1 caused by mutations in the JAG1 gene. It is not possible to diagnose this disorder biochemically. Therefore, a definitive diagnosis relies on molecular genetic testing. 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? 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 It is not possible to diagnose this disorder biochemically, therefore, a definitive diagnosis relies on molecular genetic testing. Please describe any specific ethical, legal or social issues with this particular test? Not applicable Please complete the testing criteria form. 5

6 UKGTN Testing criteria Name of Disease(s): ALAGILLE SYNDROME 2; ALGS2 (610205) Name of gene(s): Notch homolog 2 (Drosophila); NOTCH2 (600275) 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 Genetics 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 Three of the following five major clinical features Cholestasis or other liver abnormality Cardiac defect (most commonly stenosis of the peripheral pulmonary artery and its branches) Skeletal abnormalities (most commonly butterfly - vertebrate identified in AP chest radiographs) Ophthalmologic abnormalities (most common posterior embryotoxon) Characteristic facial features AND JAG1 mutation negative OR Relatives of affected individuals with a NOTCH2 family mutation 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

7 Flow pathway for Alagille syndrome testing Patient Analysis of JAG1 gene Positive Negative JAG1 MLPA (deletion) Positive Negative Suggest analysis of NOTCH2 Positive Negative 7