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 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). Properdin Deficiency Properdin P Factor Deficiency; PFD Properdin Deficiency, Type I Properdin Deficiency, Type II Properdin Deficiency, Type III Properdin is a complement protein which functions as a positive regulator of the alternative complement pathway. Properdin deficiency is the only X-linked complement deficiency. Male patients have a 250 fold greater risk of meningococcal disease than normal individuals which is often due to rare serotypes [X, Y, Z, W135, or 29E]. The mean age at onset of symptoms is years and the mortality rate from meningococcal disease has been reported to be as high a 70%. Properdin deficiency Types I and II are defined as absent or low serum properdin, respectively whilst Type III is due to the presence of dysfunctional properdin protein. Densen P, Weiler JM, Griffiss JM, Hoffmann LG. Familial properdin deficiency and fatal meningococcemia. Correction of the bactericidal defect by vaccination. N Engl J Med.;316: Linton SM, Morgan BP. Properdin deficiency and meningococcal disease-- identifying those most at risk. Clin Exp Immunol : Figueroa JE, Densen P. Infectious disease associated with complement deficiencies. Clin Microbiol Rev. 4: Schejbel L, Rosenfeldt V, Marquart H et al Properdin deficiency associated with recurrent otitis media and pneumonia, and identification of male carrier with Klinefelter syndrome Clin Immunol.;131: X-Linked Recessive Complement Factor Properdin; CFP Properdin Factor P The properdin gene is on the short arm of the X-chromosome at Xp11.4. It is 6.4kb long and contains 10 exons. Exon 1 is noncoding. The complete gene is amplified using 4 amplicons. Mutational spectrum for which you test including details of known common mutations. 14 mutations reported : Missense Nonsense Frameshifts Splicing defects Major deletions (from this laboratory, unpublished data) 1

2 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? 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 a) Index case: Fluorescent sequencing of all exons and flanking regions. Mutations confirmed by sequencing in the second direction. b) Family member: Bi-directional fluorescent sequencing of relevant gene fragment. BLAST analysis of primers. SNP analysis of primers. Optimisation of PCRs. Sequencing of normal individuals and a positive control with comparison to a reference sequence. Sequencing is used for mutation detection in the laboratory for a number of genes. YES If Yes: Number of reports issued: 2 Number of reports mutation positive: 2 Number of reports mutation negative: 0 1 Year Yes Please provide details The Immunology Department delivers the National Paediatric and adult Primary Immunodeficiency (PID) services for Wales and has one of the largest cohorts of patients in the UK. The immunology laboratory is the largest in Wales and supports the diagnosis of PID patients. Clinical services are provided as part of the Immunology Service as follows: 1) All patients are provided with information about their disorder at diagnosis. This includes patient support group information and all Wales PID patients days. 2) Clinical and interpretative advice is available from Dr S Jolles or Dr P Williams. 3) Outpatient referrals are seen in either Paediatric or Adult Immunodeficiency Clinics (every 2 weeks and weekly). 4) Inpatient assessment is available through shared care arrangements with Paediatric Infectious Disease and adult ID teams with the Department of Medicine. 5) The department has an international reputation for research into the Complement Pathway and its regulation, led by Professor BP Morgan. We provide a UKGTN service for sequencing of the IKBKG gene. The All Wales molecular genetics laboratory also provides a UKGTN service for and EDA1, EDAR EDARADD and GJB6. Our test repertoire also includes molecular testing, by sequencing of complement factors C3, C5, C6 C7 C8beta, CFP, CFI, MCP and STAT3. 2

3 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 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. Index cases:1 Family members where mutation is known: 2 Index cases: Index cases: 5/yr Family members where mutation is known:20 (more if required) Index cases: 1-3/yr Family members where mutation is known: 9 We are not aware of any other laboratories offering this service and are able to provide a national and European service. 3

4 Epidemiology Estimated prevalence of disease in the general UK population Please identify the information on which this is based The annual incidence of meningococcal disease in the general population is in the range of 1 3 per in European countries and the USA. The prevalence of complement deficiencies is higher in individuals with systemic meningococcal infections than the general population. The prevalence of complement deficiencies in sporadic cases of systemic meningococcal infection is between 1% and 15%, and even higher in recurrent cases (40%), those presenting with a family history of meningococcal disease (10%), or an unusual serotype of meninococcus (20-50%) The prevalence of properdin deficiency in the UK is unknown, but is considered very rare. Approximately 100 cases have been confirmed in Caucasians. Estimated gene frequency (Carrier frequency or allele frequency) Pettigrew HD, Teuber SS Gershwin ME Clinical significance of complement deficiencies. Ann NY Acad Sci 1173: , 2009 Fijen CA et al. Complement deficiencies in patients over 10 yrs old with meningococcal disease due to uncommon serogroups. Lancet ii: Leggiadro RJ Winklestein JA. Prevalence of complement deficiencies in children with systemic meningococcal disease. Pediatr Infect Dis 6: Ellison RT et al. Preavlence of congenital and aquired complement deficiency in patients with sporadic meningococcal disease. N Eng J Med, 308: Unknown, but considered to be very rare. Please identify the information on which this is based Estimated penetrance Please identify the information on which this is based This has not been formally established but is likely to be linked to the prevalence of the different meningitis serotypes in the population and modified by independent factors influencing the immune response. Approximately 20-50% of patients with properdin deficiency will develop meningococcal disease. Figueroa JE, Densen P. Infectious disease associated with complement deficiencies. Clin Microbiol Rev. 4: Späth PJ, Sjöholm AG, Fredrikson GN et al Properdin deficiency in a large Swiss family: identification of a stop codon in the properdin gene, and association of meningococcal disease with lack of the IgG2 allotype marker G2m(n). Clin Exp Immunol. 118: 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) Male patients presenting with either:- a)familial meningococcal disease b)severe meningococcal disease c)meningococcal disease over the age of 10 years d)fulminant lethal meningococcal disease that are caused by uncommon meningococcal serogroups, ie: W135, X, Y,Z or non-groupable meningococci. 4

5 The minimum testing criteria includes normal classical complement pathway mediated lysis. (CP50) and low or absent alternative complement pathway mediated lysis (AP50). Note, however that the alternative pathway haemolytic activity (AP50) can often lie within the normal range. A good infection history and family history and a high index of suspicion are thus extremely important factors in identifying possible cases. At-risk (for carrier) female with family history confirmed by DNA testing of the proband. 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 Test Characteristics YES NO 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. The sensitivity of fluorescent sequencing is considered to be greater than 99%. 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) The clinical sensitivity ie the number of patients within the target population that have a mutation in properdin is estimated to be >90%. Genetic heterogeneity exists with mutations in other components of the alternative pathway known to be associated with meningococcal disease, but these account for a small proportion of cases. The clinical specificity based on the current cases in the literature is approximately 100%. It is not always possible to test the functional significance of missense mutations in the absence of functional studies and/or segregation analysis. This can reduce test specificity. Predictions can be made using bioinformatic software. 5

6 Clinical validity (positive and negative predictive value in the target population) The clinical validity is high as sequencing will identify the cause of properdin deficiency and allow screening of at-risk family members including female carriers. 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. 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. The positive predictive value The positive predictive value is high because the risk of disease (meningococcal meningitis) is 250 times greater than the general population (1 3 per ). The negative predictive value The probability of not getting meningitis given normal biochemical complement testing and a negative (properdin) test is likely to be similar to the prevalence of meningitis within the general population (1 3 per ). Not applicable. The target population are families of male patients presenting with meningitis. Sequencing to identify the mutation in the proband will allow accurate identification of at-risk relatives and female carriers. The aim of diagnosis and predictive testing would be to prevent meningitis infections that have a high mortality rate. Affected relatives can be given immunology advice concerning vaccination and antibiotic prophylaxis, whilst those unaffected can be given reassurance. Carrier females can also be counselled regarding the risk in subsequent male children to allow testing to occur and a management plan put in place before meningitis. Properdin deficiency is a rare complement deficiency which increases the risk of meningococcal disease 250 fold in affected males. The mortality has been reported to be as high as 70% and the morbidity in survivors can be considerable. We have investigated a family in which 2 identical male twins. The first twin developed clinical meningitis aged 18 months and was treated with intramuscular penicillin; he was discharged from hospital after a 6 day admission. Aged 7 he developed a fever on the same day as his brother and was treated with rifampicin and remained well. His twin brother became unwell during the same episode with cough, vomiting 6

7 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? and painful feet. This progressed to become a widespread non blanching purpuric rash and despite antibiotic treatment required amputation of all 4 limbs. This was followed by a prolonged paediatric intensive care unit stay and extensive skin graphing and rehabilitation requiring 3 months in hospital. Complement screening at this time revealed abnormal alternative pathway haemolysis. These cases illustrate the potential severity and cost to the NHS of this condition. The early investigation of in depth cases, siblings and potential female carriers would identify those at risk and allow appropriate referral and immunological treatment and follow up to prevent severe meningococcal infection. While the sequela of meningococcal infection may be prevented using prophylactic antibiotics, appropriate vaccinations and an action plan in the event of infection it is clear that the costs both to the individual and the NHS may be considerable given the ongoing care the patient described will require and also the potential level of care needed for those with neurological sequela of meningococcal sepsis. Possibility of severe meningococcal disease and death in young male relatives To identify gene-positive family members and to prevent occurrences of meningitis through use of antibiotic prophylaxis. An immunological test to measure serum properdin is not available commercially. An immunoblotting method to measure serum properdin concentration is currently in development. This method could potentially be used to confirm cases of properdin deficiency Type I and II. Cases of Type III deficiency which have normal levels of dysfunctional protein would not be identified by this method. It is also not a reliable method of detecting carrierfemales,10% of whom are estimated to have serum properdin levels within the normal range. none 7

8 UKGTN Testing criteria Name of Disease(s): PROPERDIN DEFICIENCY, X-LINKED (312060) Name of gene(s): complement factor properdin; CFP (300383) 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 Immunologist Consultant Geneticist 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 Criteria 1 Male AND: Criteria 2 presenting with either:- Familial meningococcal disease Severe meningococcal disease Fulminant lethal meningococcal disease, AND: Criteria 3 Meningococcal disease by uncommon meningococcal serogroups, ie: W135, X, Y, Z or non-groupable meningococci AND at least 2 of the following Meningococcal disease over the age of 10 years Low or absent alternative complement pathway mediated lysis (AP50) Normal classical complement pathway mediated lysis (CP50) OR: At-risk (for carrier) female with family history confirmed by DNA testing OR obligate carrier female 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