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 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 Hyper IgE Recurrent Infection Syndrome: Autosomal Dominant Hyper IgE Syndrome HIES HIGE Job s Syndrome Hyperimmunoglobulin-E syndrome (HIES) is a primary immunodeficiency disorder characterized by recurrent staphylococcal skin abscesses, pulmonary infections, mucocutaneous candidiasis, skeletal and dental abnormalities and elevated serum immunoglobulin E (IgE) concentrations. HIES usually commences in infancy, but diagnosis is often delayed until childhood or even adulthood since many of the clinical features and multisystem symptoms acrue over years. Although inheritance is autosomal dominant most cases are sporadic Recurrent bacterial and fungal infections are the major cause of morbidity and mortality in HIES. Grimbacher B, Schäffer AA, Holland SM, Davis J, Gallin JI, Malech HL, Atkinson TP, Belohradsky BH, Buckley RH, Cossu F, Español T, Garty BZ, Matamoros N, Myers LA, Nelson RP, Ochs HD, Renner ED, Wellinghausen N, Puck JM. Genetic linkage of hyper-ige syndrome to chromosome 4 Am J Hum Genet Sep;65(3): Freeman AF, Davis J, Hsu AP, Holland SM, Puck JM. Autosomal Dominant Hyper IgE Syndrome.In: Pagon RA, Bird TC, Dolan CR, Stephens K, editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; Feb 23. Autosomal Dominant Gene name(s) STAT3 [Signal Transducer and Activator of Transcription 3] OMIM number for gene(s) Gene alternative names please provide any alternative names you wish listed Gene description(s) (including number of amplicons). APRF [Acute Phase Response Factor] The STAT3 gene is located on chromosome 17q21.2 and contains 24 exons. There are 2 splice variants. The complete gene is amplified using 14 amplicons. The DNA-binding domain is amplified in 5 amplicons The SRC homology 2 domain, 2 amplicons The transactivation domain, 2 amplicons 1

2 Mutational spectrum for which you test including details of known common mutations. Technical Method (s) HIES is caused by heterozygous, dominant-negative mutations in the STAT3 coding region. Single base-changes, small insertions or duplications and splicing defects have been identified. The majority of mutations are missense changes located in the DNA-binding, src homology 2, and transactivation domains encoded by exons Common mutations include R382W, R382Q,V463del and V637M. a) Index case: Fluorescent sequencing of STAT3 exons and flanking intronic sequence in the following order: 1. exons encoding the DNA binding domain ;exons encoding the src homology 2 domain; exons encoding the transactivation domain. 2. the remainder of the gene Mutations confirmed by sequencing in the second direction. 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? b) Family member: Bi-directional sequencing of relevant amplicon. BLAST analysis of primer sequence SNP surveillance of primer sequence 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: Number of reports issued:6 Number of reports mutation positive5 Number of reports mutation negative:1 6 months Yes 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. 2

3 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 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. 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 Index cases: 6 Family members where mutation is known: 1 Index cases: 10 Family members where mutation is known:10 Index cases: <10/yr Family members where mutation is known: 10 This laboratory could provide the full national need. 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 This has not been formally established for the UK. HIES is a rare disorder; about 250 cases have been published worldwide. The syndrome occurs in people of diverse ethnic backgrounds and does not seem to be more common in any specific population.the estimated frequency is <1:10 6 Grimbacher B, Holland SM, and Puck JM. Hyper-IgE syndromes. Immunol Rev 203: , Engelhardt et al J Allergy Clin Immunol. 124: The genetic etiologies of the hyper-ige syndromes are diverse. Approximately 60% to 70% of patients with hyper-ige syndrome have dominant mutations in STAT3. Woellner C et al J Mutations in STAT3 and diagnostic guidelines for hyper-ige syndrome. Allergy Clin Immunol : Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-ige syndrome. Minegishi Y, Saito M, Tsuchiya S, Tsuge I, Takada H, Hara T, Kawamura N, Ariga T, Pasic S, Stojkovic O, Metin A, Karasuyama H. Nature : % Clinical suspicion of HIES is quantified using a National Institutes of Health (NIH) scoring system, based on 19 clinical and laboratory findings. Scores of at least 40 points suggest HIES. Scores >20 and <40 with a strong clinical suspicion of HIGE will be tested. Scores below 20 suggest HIES is unlikely. Prevalence of disease will be modified by the National Institutes of Health (NIH) scoring system of individual patients, but is expected to be no less than 64% Intended Use (Please use the questions in Annex A to inform your answers) Please tick the relevant clinical purpose of testing YES NO Diagnosis Treatment Prognosis & Management Presymptomatic testing Risk Assessment for family members Risk Assessment prenatal testing 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. This can be added to the document as a separate sheet if necessary. The sensitivity of fluorescent sequencing is considered to be greater than 99%. We have identified 5 cases of HIES syndrome all of which had clinical features suggestive of HIES syndrome. We have identified a daughter of a confirmed case of HIES as not having the mutation and we have shown a patient with clinical features of HIES not to have a mutation and this patient is awaiting sequencing for DOCK8 a further cause of HIES syndrome. The sensitivity of testing is likely to be high as is the specificity in STAT3 HIES. Mutations in STAT3 account for 60-70% of AD HIES syndrome. Mutations in DOCK8 and Tyk2 have been identified in Autosomal recessive HIES. There is considerable phenotypic variability and diagnosis is often delayed until childhood or even adulthood. The positive predictive value for STAT3 HIES is likely to be high and the negative predictive value is also likely to be high. There are however a small number of patients described with HIES and mutations in DOCK8 and Tyk2. Not applicable 5

6 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) 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 is currently no diagnostic biochemical test for HIES syndrome and molecular testing offers a diagnosis in the target population as well as detecting family members earlier. The clinical scoring system is helpful but is less sensitive in the range which may occur in children who have not yet had time to accumulate all of the clinical features. The test if positive will result in the introduction of preventative measures to avoid end organ damage from infection including appropriate use of prophylactic antibiotics, vaccinations and in some cases immunoglobulin replacement. A small number of cases have responded to bone marrow transplantation. It may be necessary to treat patients to prevent bone fractures which characterise the condition. Patients will require long term immunological follow up. A molecular diagnosis of HIES allows the introduction of a management strategy aimed at preventing life threatening infections and assessing other family members. The aim is to avoid where possible repeated hospital admissions with infection particularly as one of the major pathogens in HIES is staph aureus and reduction of risk of acquiring MRSA is important. In a small number of cases bone marrow transplantation has lead to normalisation of the immunological abnormalities. We have also been able to test the daughter of a known HIGE patient who suffered from eczema, elevated IgE and infections and found her to be negative. This has allowed her to be reassured and discharged from immunology follow up while maintaining dermatology advice for her eczema. A further patient was treated with chemotherapy for elevated eosinophils before the molecular diagnosis was made. As there is currently no biochemical diagnostic test and the diagnosis relies on a clinical score the absence of a test will result in diagnoses being delayed or missed. The consequences of this are that the opportunity to begin optimal treatment will be delayed or missed with subsequent infections which may be life threatening or result in end organ damage such as bronchiectasis. In addition a negative test may allow reassurance and reduced immunology clinic visits. This test will make a clear diagnosis available to NHS patients with suspected STAT3 HIES syndrome. This will allow the introduction of optimal treatment for this severe primary immunodeficiency. There is no biochemical test currently available and the diagnosis is made on clinical grounds and using a clinical scoring system. None applicable 6

7 UKGTN Testing criteria Name of Disease(s): HYPER-IgE RECURRENT INFECTION SYNDROME, AUTOSOMAL DOMINANT (147060) Name of gene(s): signal transducer and activator of transcription 3 (acute-phase response factor); STAT3 (102582) 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 National Institutes of Health (NIH) scoring system (see below), based on 19 clinical and laboratory findings with scores of at least 40 points suggest HIES. OR Scores >20 and <40 with a strong clinical suspicion of HIGE 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. 7

8 Clinical findings Points (Circle appropriate box for each finding) Highest IgE [IU/ml] < ,000 1,001-2,000 >2,000 Skin absce sses (total #) none >4 Pneumonias (X-ray none >3 proven, total #) Parenchymal lung absent bronchiectasis pneumatocele abnormalities Other serious infection none severe Fatal infection absent present Highest eosinophils/ul < >800 Newborn rash absent present Eczema (worst stage) absent mild moderate severe ll Sinusitis, otitis (# times in >6 worst year) Candidiasis none oral, vaginal fingernail systemic Retained primary teeth none >3 Scoliosis, max curve <10º 10-14º 15-20º >20º Fractures with little none 1-2 >2 trauma Hyperextensibility absent present Characteristic face absent mild present Increased nose width (interalar distance) <1 SD 1-2 SD >2 SD High palate absent present Midline anomaly absent present Lymphoma absent present Young age add-on >5 y 2-5 y 1-2 y <1 y 8