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Proposal form for the evaluation of a genetic test for NHS Service Gene Dossier Test – Disease – Population Triad Disease – name Hereditary Angioedema [HAE] OMIM number for disease 106100 Disease – alternative names please provide any alternative names you wish listed Hereditary Angioneurotic Edema; HANE, Deficiency of C1 Esterase Inhibitor Hereditary Angioedema Type I, Hereditary Angioedema Type II Disease – please provide a brief description of the disease characteristics Hereditary angioedema (HAE) is a rare single gene disorder characterised by episodic bouts of well circumscribed, non urticarial swelling of the subcutaneous, submucosal and subepithelial tissues. Patients may experience swelling of the abdomen, face, genitalia and extremities, abdominal pain, nausea, vomiting, or diarrhoea as well as life-threatening swelling of the larynx. The 2 main forms of HAE (Types 1 and 2) are caused by mutations in the SERPING1 gene. 85% cases of HAE are classified as Type I and have quantitative and functional deficiency, whereas in Type II, the C1 esterase inhibitor levels are normal or elevated, but the protein is nonfunctional. The 2 types are clinically indistinguishable. Autosomal dominant. Very rare cases of homozygous deficiency. SERPING1 (serpin peptidase inhibitor, clade G, member 1) Disease - mode of inheritance Gene – name(s) OMIM number for gene(s) Gene – alternative names please provide any alternative names you wish listed 606860 COMPLEMENT COMPONENT 1 INHIBITOR; C1NH; C1I; C1INH Gene – description(s) (including The SERPING1 gene has a chromosomal location of 11q12.1 The 17-kb gene contains 8 exons that include 7 coding exons and number of amplicons). a non-coding first exon (Carter et al, 1988). The encoded protein contains 500 amino acids. It is amplified in 7 amplicons for sequencing and 6 amplicons for QMPSF. Mutational spectrum for which you HAE is a disease of extreme allelic heterogeneity. Missense, test including details of known nonsense, splicing mutations and small deletions/insertions are common. Large gene rearrangements, including partial gene common mutations. deletions and (less frequently) partial duplications, account for approximately 20% and are thought to be due to unequal recombination between Alu repeats present within introns. a) Index case: Fluorescent sequencing of the promoter region, all Technical Method (s) codons and flanking regions. Mutations confirmed by sequencing in the second direction. If no mutation found, large genomic rearrangements are screened by Quantitative Multiplex PCR of Short Fluorescent Fragments [QMPSF]. and confirmed by sequencing across QMPSF primer sequence b) Family member: Bi-directional fluorescent sequencing or QMPSF analysis of relevant gene fragment. 1 Approval Date: Sept 2010 Submitting laboratory: Cardiff SAS Porphyria Copyright UKGTN © 2010 Validation Process Note: please explain how this test has been validated for use in your laboratory Are you providing this test already? Blast analysis of primer sequences 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. Optimisation of QMPSF following published method. Single and contiguous exon deletions confirmed by sequencing through primer regions or using nested primers. 23 reports If yes, how many reports have you produced? Please give the number of mutation positive/negative samples you have reported 22 positive, 1 negative. This index case has been subsequently given an alternative explanation for the angioedema. For how long have you been providing this service? 2 years Is there specialised local clinical/research expertise for this disease? 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. This cohort includes over 40 patients with hereditary angioedema. 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. Are you testing for other genes/diseases closely allied to this one? Please give details There has been a long-standing research interest in both the treatment and diagnosis of immunodeficiency in the department. 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 (Clouston disease) Our test repertoire also includes molecular testing, by sequencing of complement factors C3, C5, C6 C7 C8beta, CFP, MCP and STAT3. 2 Approval Date: Sept 2010 Submitting laboratory: Cardiff SAS Porphyria Copyright UKGTN © 2010 Index cases: 8 Your Current Activity If applicable - How many tests do you Family members where mutation is known: 4 currently provide annually in your laboratory? Your Capacity if Gene Dossier Index cases: 16 approved Family members where mutation is known: 20 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 Index cases: 2-5 tests will be required nationally (UK Family members where mutation is known: 2-5 wide)? Please identify the information on It has been estimated that there are approximately 800 HAE which this is based patients in the UK and a small proportion (4-5/yr) of these will be referred for genetic testing. (see below for those cases where molecular testing is recommended) We are not aware of any other laboratories offering this service in National Activity the UK and are able to provide a national service (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”. Epidemiology Estimated prevalence of disease in the general UK population Please identify the information on which this is based There is no data available to give an accurate estimate of the prevalence of Hereditary Angioedema in the UK population. The minimal prevalence of HAE in Denmark is approximately 1.41 per 100 000 inhabitants and studies in Spain and Norway suggest minimal prevalence from 1·09 to 1·51 per 100 000 inhabitants. Estimation of disease prevalence in American is 1:50000. Bygum A.Hereditary angio-oedema in Denmark: a nationwide survey. Br J Dermatol. 1611153-8 2009 Weiler CR Van Dellen RG Genetic Test Indications and Interpretations in Patients With Hereditary Angioedema. Mayo Clin Proc 81:958-72 2006 3 Approval Date: Sept 2010 Submitting laboratory: Cardiff SAS Porphyria Copyright UKGTN © 2010 Estimated gene frequency (Carrier frequency or allele frequency) Please identify the information on which this is based This has not been formally established. HAE is considered to be a highly penetrant disorder. Approximately 33-50% of cases of HAE present without a family history but are mostly the result of sporadic mutation.Therefore gene frequency is likely to be similar to disease frequency. Weiler CR Van Dellen RG Genetic Test Indications and Interpretations in Patients With Hereditary Angioedema. Mayo Clin Proc 81:958-72 2006 Estimated penetrance Please identify the information on which this is based Pappalardo E et al. Frequent de novo mutations and exon deletions in the C1inhibitor gene of patients with angioedema.J Allergy Clin Immunol106:1147-54. 2000 Penetrance is considered to be high in adults, although some patients have minimal or no symptoms for years before they become symptomatic. Pappalardo E et al. Frequent de novo mutations and exon deletions in the C1inhibitor gene of patients with angioedema. J Allergy Clin Immunol106:1147-54. 2000 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) The majority of diagnoses of HAE will be made by biochemical complement testing (C3, C4, C1INH concentration and functional C1INH). The target population for whom molecular testing is of particular utility are cases of angioedema where the results of biochemical testing are equivocal. Positive or negative confirmation of HAE is of equal importance in providing the appropriate treatment. This group will include: Population 1 Children under the age of 1, with equivocal biochemistry who present with angioedema without a family history. Population 2 At-risk relatives, particularly young children, in families with a history HAE before onset of clinical symptoms in whom biochemical testing has not been diagnostic. Estimated prevalence of disease in the target population Population 1 The prevalence of the disease in the target population cannot be estimated. Population 2 The prevalence of the disease amongst at-risk relatives is expected to be 50% 4 Approval Date: Sept 2010 Submitting laboratory: Cardiff SAS Porphyria Copyright UKGTN © 2010 Intended Use (Please use the questions in Annex A to inform your answers) Please tick the relevant clinical purpose of testing YES Diagnosis √ Treatment √ Prognosis & Management √ Presymptomatic testing √ Risk Assessment for family members √ NO √ Risk Assessment – prenatal testing Test Characteristics An a lytic a l s e n s itivity a n d s p e c ificity 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 analytical sensitivity of fluorescent sequencing is believed to be greater than 99%. The analytical sensitivity of QMPSF is comparable to other methods including MPLA (>95% for those fragments analysed). Clinical sensitivity and specificity of test in target population Clinical sensitivity 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 with clinically and biochemically defined HAE and have a mutation in the SERPING1 gene is estimated to be 82-94%. In our laboratory it is 93%., based on our analyses of index cases. (see above) Clinical specificity. Approximately 100% Many disease causing mutations in HAE are novel missense mutations (30-40%). It is not always possible to test the functional significance of these in the absense of functional studies and/or segregation analysis. This can reduce test specificity. Predictions can be made using bioinformatic software, including PolyPhen, by SERPIN sequence alignments or by reference to the C1Inhibitor gene mutation database. [http://hae.enzim.hu/] Gösswein T et al Mutational spectrum of the C1INH (SERPING1) gene in patients with hereditary angioedema. Cytogenet Genome Res. 121:181-8 28. 2008 Pappalardo E et al Mutation screening of C1 inhibitor gene in 108 unrelated 5 Approval Date: Sept 2010 Submitting laboratory: Cardiff SAS Porphyria Copyright UKGTN © 2010 families with hereditary angioedema: functional and structural correlates.Mol Immunol 45:3536-44. 2008 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). Positive predictive value Penetrance is high, however the disease phenotype is very variable and there are as yet no clear association of genotype with severity. Negative predictive value Family members in whom a familial mutation has been excluded are no longer at risk of developing HAE, although the possibility of sporadic HAE cannot be excluded. 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. Not applicable Clinical utility of test in target population (Please refer to Appendix A) Molecular genetic testing of cases of angioedema with a family history but with equivocal biochemical results and testing of infants, in whom biochemical testing may be unreliable, make up the target population. Please provide a description of the clinical Molecular genetic analysis is an effective way of care pathway. confirming the clinical diagnosis and identifying mutation carriers early on before any clinical manifestation becomes apparent How will the test add to the management of the patient or alter clinical outcome? The test will allow the introduction of a clear treatment plan in keeping with HAE consensus guidelines. This aims to reduce the frequency and severity of attacks using prophylaxis as well as putting in place a plan for the acute, life-threatening attacks involving the airway or gastrointestinal tract. With home therapy patients are provided with home C1 esterase inhibitor supplies which enable them to respond 6 Approval Date: Sept 2010 Submitting laboratory: Cardiff SAS Porphyria Copyright UKGTN © 2010 more rapidly to attacks and plan travel and jobs which might take them away from their local emergency department. Increasingly clarity of diagnosis is required to facilitate most appropriate use expensive treatment interventions. In hereditary angioedema biochemical testing offers a diagnostic approach for the majority of cases however in some the biochemistry results may be equivocal and in the very young biochemical testing may be unreliable. In these circumstances molecular testing allows a diagnosis to be made and hence prophylactic acute and home therapy management plans can be put into place. The immunology department at UHW has one of the largest cohorts of hereditary angioedema places in Wales and a failure to make a diagnosis has a major impact both on the quality of life of the patient, the ability to retain a job and of course may lead to death. We have audited all of the hereditary angioedema patients in Wales and identified a diagnostic delay of on average 11.1 years. Prior to the diagnosis being made 1 patient would lose between 30-40 days of work per year and had all of his teeth extracted as he felt these were causing his swellings. In addition, many patients may undergo unnecessary abdominal surgery as the attacks may present with an acute abdomen and some may have tracheostomies and be repeatedly treated for an allergic reaction with adrenaline, antihistamine and steroids. There is a considerable cost to the NHS of attendance at emergency departments and admissions to hospital which would be preventable with appropriate diagnosis and treatment which would also lead to a reduction in the impact on for example days of work lost, time lost from school and quality of life. Failure to diagnose HAE and thus put in place the prophylactic, acute and home therapy management plans and immunological follow up to avoid life threatening airway and gut attacks and improve quality of life. 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? The emergency treatments available for HAE are costly (£600-1400/ swelling episode). A positive diagnosis will clarify the care pathway and the appropriate use of expensive HAE medication whilst a negative test would require no further clinical appointments for a presumed diagnosis of HAE. Biochemical and Immunology investigations demonstrating low serum C4, low C1INH (Type I) or low functional C1INH (Type II) are available and will provide a diagnosis in the majority of cases However biochemical analysis of C1INH concentration and function in the very young is unreliable because of the lack of an appropriate standard range. None 7 Approval Date: Sept 2010 Submitting laboratory: Cardiff SAS Porphyria Copyright UKGTN © 2010 UKGTN Testing criteria Name of Disease(s): ANGIOEDEMA, HEREDITARY; HAE (106100) Name of gene(s): serpin peptidase inhibitor, clade G (C1 inhibitor), member 1; SERPING1 (606860) Patient name: Date of birth: Patient postcode: 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 Recurrent non-urticarial angioedema, usually of gradual onset involving the peripheries, gut or larynx, usually of gradual onset and lasting 1-5 days and presenting without a family history AND Equivocal serum C1INH concentration or function OR Young children with a family history of Hereditary Angioedema AND Equivocal serum C1INH concentration or function 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 Approval Date: Sept 2010 Submitting laboratory: Cardiff SAS Porphyria Copyright UKGTN © 2010