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 Parkinson disease 8, automsomal dominant 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) 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 Parkinson disease 8 Dardarin LRRK2 related Parkinson disease (PD) LRRK2-related PD is a typically late onset PD and the age of onset is after 50 years. The clinical features are indistinguishable from those of idiopathic PD and include, asymmetric tremor at rest and/or bradykinesia (slow movement), muscle rigidity, postural instability and gait abnormalities. Autosomal dominant Leucine rich repeat kinase 2 (LRRK2) Parkinson disease 8 (PARK8) LRRK2 gene is mapped to chromosome 12q12, contains 51 exons spanning 144 kb and encodes a 2527 amino acid protein with a molecular mass of 250kD. At least 7 mutations are known to be pathogenic. The c.6055g>a (p.gly2019ser) is the most common LRRK2 mutation and accounts for approximately % of simplex PD cases and up to 30% of familial PD cases (varying between different populations). The other 6 mutations are; c.4321c>t (p.arg1441cys), c.4321c>g (p.arg1441gly), c.4883g>c (p.arg1628pro), c.5096a>g (p.tyr1699cys), c.6059t>c (p.ile2020thr) and c.7153g>c (p.gly2385arg). References: Williams-Gray et al (2006) J Neurol Neurosurg Psychiatry;77:665 7 and Gene reviews MLPA analysis only for the c.6055g>a (p.gly2019ser) mutation. Laboratory validation of probe sequences (SNP checking) and use of correct reference sequences to ensure that the appropriate sequence is analysed. MLPA assay further validated using known normal and mutation controls provided by our research colleagues. 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 For how long have you been providing this service? 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)? Please identify the information on which this is based Y If Yes: Number of reports issued: 19 The 19 reports refer the number of reports issued when the c.6055g>a (p.gly2019ser) mutation test alone has been requested. As testing is carried out using the SALSA MLPA kit P051 Parkinson mix 1, we also report on the presence or absence of the p.gly2019ser mutation within our PARK2 reports unless the disease shows a recessive mode of inheritance. Number of reports mutation positive: (PARK2 negative but LRRK2 positive as explained above ) Number of reports mutation negative: 16 Since February 2009 Yes Please provide details Dr. Huw Morris, Senior Lecturer in Neurology is engaged in a clinical epidemiological project on young onset Parkinson s disease and is carrying out research into the genetics of young onset Parkinson s disease. He will assist with review of requests and reports as required Yes We also provide a screening service for the PARK2 gene, implicated in early onset Parkinson s disease. Index cases: 14 Family members where mutation is known: 2 Index cases: 14 Family members where mutation is known: 2 Index cases: ~ Assuming that the Institute of Neurology, Neurogenetics Unit, Queen Square, London has a similar uptake. Family members where mutation is known: ~ 15; could be more if parental samples are available followed by cascade screening. National Activity (England, Scotland, Wales & Northern Ireland) If your laboratory is unable to provide the full national need please could you provide information on This service is also provided by the Institute of Neurology, Neurogenetics Unit, Queen Square, London WC1N 3BG. 2

3 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

4 Epidemiology Estimated prevalence of disease in the general UK population Please identify the information on which this is based Estimated gene frequency (Carrier frequency or allele frequency) Please identify the information on which this is based Estimated penetrance Please identify the information on which this is based 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 Parkinson disease (PD) is /100,000. Schrag et al. BMJ Jul 1; 321(7252): 21-2 The LRRK2, c.6055g>a (p.gly2019ser) mutation is the most frequent of the LRRK2 mutations and is found in 0.5% to 13% sporadic PD and in 5% to 30% of familial PD (varying between different populations). Dachsel and Farrer, Arch Neurol; 67(5): ; Williams-Gray et al. (2006) J Neurol Neurosurg Psychiatry;77:665 7 and Gene reviews ( Disease penetrance is age dependant and increases from ~20% at 50 years of age to 80% at 70 years of age. Dachsel and Farrer, Arch Neurol; 67(5): The test is indicated for: a) Patients with Jewish or North African Berber ancestry. b) Patients in PD families showing an autosomal dominant inheritance pattern. c) Patients with late onset sporadic PD 15% of Ashkenazi Jews with PD have the LRRK2, c.6055g>a (p.gly2019ser) mutation. This is also the most common mutation in North African Arab-Berbers with PD. Approximately 5% of Western European/North American patients with familial Parkinson disease ( 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 4

5 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). 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. >99% There is considerable genetic heterogeneity in familial and young onset Parkinson disease. The gold standard for diagnosis is the application of the Queen Square brain bank clinical diagnostic criteria which have been shown to have a high correlation with post-mortem pathology. The primary aim of genetic testing in PD is to delineate the inheritance of the disease. Clinical sensitivity Parkin Young onset disease 20% LRRK2 p.gly2019ser Familial disease 5% It is not possible to give meaningful analyses of positive or negative predictive values for LRRK2 testing using either the total PD or the total mutation positive PD population since i) these gene changes are numerically rare causes of PD, and ii) there is no alternative way to identify parkin or LRRK2 positive disease other than genetic analysis. The situation is different to genetic diseases such as NF-1, where there are clinical diagnostic criteria and genetic homogeneity. Approximately 10% of Parkinson disease in the UK is genetic. However a positive genetic test has extremely high predictive value for individual cases and their families. See attachment 5

6 This can be added to the document as a separate sheet if necessary. 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) The main role of parkin testing will be in enabling accurate genetic counselling. Although Parkinson disease is usually a clinical diagnosis in the younger age group there may be uncertainty between a diagnosis of Parkinson s disease or dopa responsive dystonia. This has implications for response to treatment and the development of treatment related complications (DRD patients do not develop treatment related complications). Parkinson disease may occur in sporadic, autosomal dominant or autosomal recessive forms and this test will be diagnostic for one of the commonest form of autosomal dominant Parkinson disease. Parkinson disease may occur in sporadic, autosomal dominant or autosomal recessive forms. The identification of a LRRK2, c.6055g>a (p.gly2019ser) mutation will allow appropriate genetic counselling to the patient and their families. LRRK2 analysis will allow appropriate genetic counselling and remove the need for further genetic investigations. E.g. The cost to test for the c.6055g>a (p.gly2019ser) mutation at present is 160 and a positive result here will prevent further analyses such as a PARK2 gene screen which costs 680. More money spent on other investigations and the failure to direct patients to newly developing therapies. E.g. Lee et al. (2010) have recently shown that inhibitors of LRRK2 kinase activity reverse/ prevent the neurotoxicity caused by LRRK2 gene mutations (Nature Medicine, 16; ) Currently LRRK2 mutation status does not lead to any change in treatment. Approximately 5% of PD patients have dopamine transporter scanning (cost 500) to confirm the diagnosis of PD, which may be avoided by genetic testing. Lack of a genetic confirmation of familial Parkinson s disease will lead to inaccurate genetic counselling and advice. Dopamine transported scanning is available as a routine NHS test and is indicated to distinguish between essential tremor and PD, drug induced parkinsonism and PD and Lewy body dementia and Alzheimer disease Parkinson disease is multifactorial disorder and whilst only a small number of cases are hereditary, there are several genes implicated in familial PD. Hence, a positive result from this test will not only inform the patient and clinicians with regards to his management, it will also enable appropriate genetic counselling. 6

7 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 are no alternative means of diagnosing LRRK2- related Parkinson disease other than molecular diagnosis. N/A 7

8 UKGTN Testing Criteria Name of Disease: PARKINSON DISEASE 8, AUTOSOMAL DOMINANT; PARK8 (607060) Name of gene(s): leucine-rich repeat kinase 2; LRRK2 (609007) 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 Neurologists Clinical Geneticists Tick if this refers to you. Minimum criteria required for testing to be appropriate as stated in the Gene Dossier: Criteria Late onset Parkinson s disease over the age of 50 AND Autosomal dominant family history OR At risk family members with known mutation Tick if this patient meets criteria If the sample does not fulfil these criteria and you still feel that testing should be performed please contact the laboratory to discuss testing of the sample 8