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 Mucopolysaccharidosis type 3B (MPS3B, MPSlllB) Sanfilippo syndrome B N-acetyl-alpha-D-glucosaminidase deficiency NAGLU deficiency MPS3B is one type of 4 related autosomal recessive lysosomal storage disorders caused by impaired degradation of heparan sulfate (found in the urine of affected patients). The first symptoms appear between the ages of 2 and 6 years, with behavioural disorders (hyperkinesia, aggressiveness) and intellectual deterioration, sleep disorders and very mild dysmorphism. The neurological involvement becomes more prominent around the age of 10 years with loss of motor milestones and communication problems. Seizures often occur after the age of 10. Prognosis is poor but may be longer for type 3B & D than type 3A OMIM number for disease # Gene name and description (please provide any alternative names you wish listed) Alpha-N-acetylglucosaminidase (NAGLU) MPS IIIB is caused by deficiency of the alpha-nacetylglucosaminidase (NAGLU) enzyme. OMIM number for Gene * Mutational spectrum for which you test Missense, nonsense and small insertion and deletion mutations identified throughout the gene. Currently 115 mutations of this type listed on the Human Gene Mutation Database, Cardiff ( Recurrent mutations have been described albeit at low frequencies. As published figures are based on low patient numbers and recurrent mutations appear to account for a small percentage of disease alleles we would not offer carrier testing to non-consanguineous family members of MPSIIIB carriers. Given the low carrier frequency in the general population we also do not feel that full sequencing testing is justified in non-consanguineous family members of MPSIIIB carriers. Technical Method (s) Validation Process Note please explain how this test has been validated for use in your laboratory Full sequence testing of all 6 coding exons (in 10 fragments). Family mutations: PCR and restriction enzyme digest or sequencing Sequencing is a standard analytical method used in the laboratory for a range of diagnostic services requiring mutation detection. The laboratory participates in external quality assessment sequencing schemes 1

2 Are you providing this test already? If yes, how many reports have you produced? Yes 3 x full sequence analysis, 8 x family mutation 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 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 January 2007 Yes No Please provide details Great Ormond Street Hospital is one of several national centres designated by the National Commissioning Group to co-ordinate therapy for patients with various lysosomal storage disorders. Dr Clare Beesley, now working as a Clinical Scientist in our department, carried out research testing of patients with MPS3B at the Institute of Child Health, London (Beesley, C (2000) J Med Genet 37: ). The Biochemistry Department at Great Ormond Street Hospital has considerable expertise in the diagnosis of MPS3B (and other lysosomal storage disorders) Yes. We currently carry out testing for many other lysosomal storage disorders such as Fabry disease, Gaucher disease and Mucopolysaccharidosis types 1 and 2. We also test for MPS3 type A (SGSH gene). Much of this testing was originally set up at the Institute of Child Health, London where there is considerable research experience. As mentioned above, there is also considerable clinical experience at Great Ormond Street Hospital of lysosomal disorders. Two confirmed cases diagnosed by enzyme analysis at Great Ormond Street Hospital in Only biochemically confirmed cases will be tested. Two cases were detected by the biochemistry lab at Great Ormond Street Hospital in We would anticipate that several families tested on a research basis may require confirmatory testing in our lab. 2

3 Epidemiology Estimated prevalence of disease in the general UK population Please identify the information on which this is based 1 in 86,000 Netherlands (Poorthuis BJ et al. (1999) Hum Genet 105(1-2): ) 1 in 58,000 - Western Australia for all forms Sanfilippo of which half were type B (Nelson J et al. (2003) Am J Med Genet 123(3): ) p.tyr140cys, p.arg297x and p.arg626x were all identified in more than one unrelated patient and together accounted for 25% of mutant alleles Beesley C et al. (1998) J Med Genet 35(11): 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 Autosomal recessive. Estimating from above incidence figures, carrier frequency would be between 1 in 120 and 1 in 150 Little published information. In cases with very low or absent enzyme activity (which would be the only cases we would accept) there is likely to be close to 100% penetrance. Target Population The essential clinical or family history features defining the target population must be described. Full sequencing analysis will be offered to patients with biochemically confirmed MPS3B (direct analysis of the NAGLU enzyme) or parents of a confirmed MPS3B patient (where no DNA sample is available from the index case) (C)-Testing Criteria Estimated prevalence of disease in the target population Close to 100% in biochemically confirmed cases. We would recommend that biochemical testing is carried out in an experienced laboratory where direct enzyme analysis is possible to differentiate the four sub-types of MPS3 (types A, B, C & D). This expertise is available in the Chemical Pathology department, Great Ormond Street Hospital. 3

4 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 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) Little information available on mutation pickup in biochemically confirmed cases. Papers such as that by Beesley (Beesley, C (2000) J Med Genet 37: ) generally identify mutations in all patients tested using similar methods as that proposed in this document. Clinical specificity very high in a patient with normal enzyme activity. 4

5 Clinical validity (positive and negative predictive value in the target population) All patients (index cases) tested will be biochemically confirmed as affected. 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. Testing would primarily be for disease confirmation, carrier testing, prenatal diagnosis and potentially PGD if appropriate. Treatment is mainly supportive (gene therapy is under investigation in animal models). (B)-Testing Criteria How will the test add to the management of the patient or alter clinical outcome? Testing would primarily be for disease confirmation, carrier testing and prenatal diagnosis. Treatment is mainly supportive. 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 Carrier testing would be impossible without an identified mutation due to overlap of normal and carrier enzyme levels. Enzymology is available and is a definitive test. However, mutation analysis may offer prognostic information and is the only reliable way of offering carrier testing. The ease of transport/storage of DNA samples may offer advantages over enzyme testing in prenatal diagnosis (where causative mutations have been identified). Common methods and reagents (i.e. not disease specific) are also used for all prenatal tests in this laboratory. 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 PATIENTS WITH BIOCHEMICALLY CONFIRMED MPS3B OR PARENTS OF BIOCHEMICALLY CONFIRMED CASE WHERE NO SAMPLE FROM THE INDEX CASE CAN BE OBTAINED Note testing is not offered to un-related partners of carriers WHAT TYPE AND LEVEL OF PROFESSIONAL OR REFERRER DO YOU ACCEPT SAMPLES FROM? CONSULTANT METABOLIC CLINICIAN CLINICAL GENETICIST PAEDIATRIC NEUROLOGIST PLEASE PROVIDE DETAILS OF HOW REFERRALS WILL BE ASSESSED FOR APPROPRIATENESS? CLINICAL SCIENTIST WILL CONFIRM THAT BIOCHEMICAL CONFIRMATION OF MPS3B HAS BEEN OBTAINED HOW MANY TESTS DO YOU EXPECT TO PERFORM ANNUALLY? In 2007 two cases confirmed 7

8 UKGTN Testing criteria: Name of Disease(s): MUCOPOLYSACCHARIDOSIS TYPE IIIB (252920) Name of gene(s): N-acetylglucosaminidase, alpha- (Sanfilippo disease IIIB); NAGLU (609701) 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 Specialists Paediatric Neurologists Tick if this refers to you. Minimum criteria required for testing to be appropriate as stated in the Gene Dossier: Criteria Clinical diagnosis of MPS 3B AND Proven decrease in alpha-n-acetyl glucosaminidase (NAGLU) enzyme levels. At risk relatives where a family mutation has been found. 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