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 Epileptic encephalopathy, early infantile 4. OMIM number for disease Disease alternative names EIEE4, Ohtahara syndrome. please provide any alternative names you wish listed Disease please provide a brief Severe seizure disorder beginning in the first few months of description of the disease life, plus severe mental retardation characteristics Disease - mode of inheritance Autosomal dominant, vast majority of cases have de novo mutations. Gene name(s) STXBP1 OMIM number for gene(s) Gene alternative names Syntaxin binding protein 1. please provide any alternative names you wish listed Gene description(s) (including 20 exons, 1887 nucleotides. number of amplicons). Mutational spectrum for which Frameshift, nonsense, missense and splice mutations. you test including details of known common mutations. Technical Method (s) Bi-directional sequencing of the whole of the coding region plus 20 bp of flanking intron (20 fragments). 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? Is there specialised local clinical/research expertise for this disease? The primer sets used have been SNP-checked, validated to ensure that the full coding sequence was covered, and optimised to work robustly under diagnostic conditions. Y If Yes: Number of reports issued: 12 Number of reports mutation positive: 1 Number of reports mutation negative: 10, plus 1 unclassified variant. A research project conducted in our laboratory sequenced 28 patients with infantile spasms for STXBP1 mutations and detected 1 pathological mutation. 9 months Yes Dr Hayley Archer Please provide details 1

2 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. MECP2, CDKL5, ARX, FOXG1, TCF4, SLC9A6 Index cases: 15 Family members where mutation is known: 0 Index cases: 20 Family members where mutation is known:10 Index cases: 20 Family members where mutation is known: 10 Full national need can be provided. We also expect referrals from outside the UK 2

3 Epidemiology Estimated prevalence of disease in the general UK population Estimated gene frequency (Carrier frequency or allele frequency) Estimated penetrance Population frequency of benign familial neonatal seizures (BFNS), is estimated to be 14.4 per 10,000 live births, the frequency of STXBP1 mutations amongst this group is unknown, but likely to be low. n/a, mutations are de novo. >95%, no asymptomatic carriers of STXBP1 mutations have been identified to date. 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 Patients with a clinical diagnosis of EIEE with a burstsuppression pattern on EEG. Infantile spasms/early onset epilepsy and severe mental retardation. Also atypical Rett syndrome (early onset seizure variant). Patients may have tested negative for CDKL5 or ARX. STXBP1 mutations have been reported in up to 1/3 of patients with clinical EIEE. Ref. Saitsu H et al (Epilepsia (2010) 51(12) p ) 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 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. 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. >95% (sequence analysis of entire coding region) Up to 33% of patients with clinical EIEE have mutations in STXBP1. The mutation detection rate in patients with infantile spasms/west syndrome is significantly lower. Specificity =>99%. Positive predictive value: High A positive test result in the majority of cases indicates confirmation of diagnosis. Negative predictive value: Low Ohtahara phenotype: Test STXBP1 first, then CDKL5, then ARX West syndrome female: Test CDKL5 first, then ARX common expansion, then STXBP1 then ARX full screen. West syndrome male: Test ARX common expansion first, then STXBP1, CDKL5 then ARX full screen. Identification of the genetic basis of the epileptic encephalopathy will aid genetic counselling and permit families to make informed reproductive choices for the future. 4

5 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) 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? Molecular diagnosis offers explanation of affected case and clarity about reproductive risks. This allows families to make informed choices for the future. Patients are less likely to have ongoing invasive investigations once a cause for their epileptic encephalopathy has been identified. For example, procedures under general anaesthetic such as brain MRI, lumbar punctures, muscle biopsies and others. Children with profound LD and epileptic encephalopathy will continue not to have an explanation. Families will not be able to make informed choices about future children. Future children may be born with the same devastating illness, with the resultant impact on the family. Will provide information about mode of inheritance of this severely disabling condition which will allow the parents to have confidence to add to their family. No None 5

6 UKGTN Testing Criteria Name of Disease(s): EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 4; EIEE4 (612164) Name of gene(s): syntaxin binding protein 1; STXBP1 (602926) 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 Paediatric neurologist Tick if this refers to you. Minimum criteria required for testing to be appropriate as stated in the Gene Dossier: Criteria Criteria 1 seizures with onset in infancy before 6 months AND Criteria 2 abnormal EEG pattern (such as Suppression bursts (S-B), hypsarrhythmia or multifocal spike) AND Criteria 3 marked developmental delay At risk family members where mutation is known 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