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) Glucocorticoid-remediable aldosteronism: GRA Glucocorticoid-suppressible hypertension: GSH Familial hyperaldosteronism type I (A)-Testing Criteria An autosomal dominantly inherited form of hypertension associated with hyperaldosteronism. Clinical suspicion is heightened by a family history of premature haemorrhagic CVA, marked hypokalaemia on thiazides or failure of BP to respond to 3 agents. A hypotensive response to corticosteroid administration is expected. The biochemical hallmark is presence in the urine of excess 18- hydroxysteroids OMIM number for disease #103900 Gene name and description (please provide any alternative names you wish listed) CYP11B2/CYP11B1 (unequal crossover) Unequal crossover between - cytochrome P450, family 11, subfamily B, polypeptide 2; CYP11B2 - cytochrome P450, family 11, subfamily B, polypeptide 1; CYP11B1 OMIM number for Gene CYP11B2-124080 CYP11B1-610613 The 11β-steroid hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes lie close together on chromosome 8q21. Unequal crossover upstream of exon 5 during meiosis generates a third, chimeric allele between the two genes that brings CYP11B2 under the regulatory control of ACTH (the usual secretagogue of CYP11B1). The chimera can be detected by long-range PCR using one primer from each gene. Mutational spectrum for which you test Technical Method (s) Unequal crossover upstream of exon 5, detected by specific long-range PCR. Long-range PCR analysis of index cases with definite or possible GRA using primer pair specific for crossover gene product. Testing at risk relatives once a product has been identified 1
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? The test has been set up in the laboratory and validated using known cases previously diagnosed by Southern Blot. Yes 1! 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)? 1 x Normal Research basis only to date Yes X No Please provide details Yes, there is clinical expertise at Addenbrooke s both within the Division of Renal Medicine, which receives referrals from around the UK and Europe for clinical and genetic advice in a multidisciplinary Renal Genetics and Tubular Disorders Clinic (Prof. Fiona Karet, Drs. Richard Sandford and Anthony Norden) and in the Clinical Pharmacology Unit (Prof. Morris Brown and Dr. Kevin O Shaughnessy. In addition, the molecular analysis of the relevant genes is already done on a research basis. Testing for Liddle syndrome, another dominantly inherited hypertensive condition, has been approved, together with Gitelman syndrome, a receive hypotensive disorder. Tests for similar conditions are planned. 10 predicted per year None provided at present. Clinical need for these tests is not being met from any source. 10 predicted per year based on clinical experience here and of colleagues. 2
Epidemiology Estimated prevalence of disease in the general UK population 1:1,000 hypertensives Estimated gene frequency (Carrier frequency or allele frequency) Fogari et al, Hypertens Res. 30:111-7, 2007; also anecdotal based on clinical discussions at national meetings As above. Autosomal dominant transmission Estimated penetrance Literature and clinical experience > 90% Rich et al. Ann Intern Med. 116:813-20, 1992 and other published cases Target Population The essential clinical or family history features defining the target population must be described. 1. Clinically affected individuals, assessed by renal or general physician: hypertension with biochemical evidence of primary hyperaldosteronism and positive family history. 2. At-risk relatives of index cases (C)-Testing Criteria Estimated prevalence of disease in the target population 1. > 90% in population of clinically diagnosed definite group (no estimates available for the clinically diagnosed likely and unlikely groups) 2. 50% in population of siblings of affected individuals 3. 50% in offspring of affected individuals 4. 50% in parents of affected individuals 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 3
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. On the basis of current evidence we estimate that the analytical specificity and sensitivity of the diagnostic PCR assay will be greater than 98%. 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) From current knowledge it is expected that sensitivity = 98-100% specificity = 98-100% 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). 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 Estimated PPV > 98% NPV > 98% 4
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. (B)-Testing Criteria How will the test add to the management of the patient or alter clinical outcome? Chronic hypertension has adverse implications for future end-organ damage and overall survival. GRA is not only associated with severe hypertension, but is also particularly associated with premature death from haemorrhagic CVA GRA is an unusual type of hypertension because while like the other primary forms it can be severe and difficult to treat with standard antihypertensive agents, it is the only one that can, and should, be specifically treated with corticosteroids. Giving steroids to other hypertensives can be dangerous. Achieving the correct diagnosis not only permits prompt institution of the correct therapy, but allows testing of appropriate relatives for the identified genetic abnormality. Some of these relatives will be asymptomatic and not yet be diagnosed clinically. However, asymptomatic GRA has implications particularly for the occurrence of life-threatening CVA. To make the diagnosis biochemically can be difficult, requiring a steroid suppression test that has only intermediate sensitivity, and could be hazardous in the non-gra hypertensive. 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? The benefit of a true negative result for an at-risk family member is the reassurance that the individual has the normal population risk for hypertension in general and GRA in particular, and does not require long-term monitoring/clinic attendances. 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 Yes Use of clinical and biochemical parameters, but these are either not pathognomonic i.e. lack specificity (high aldosterone, low renin) or can lack sensitivity (steroid suppression, urine 18-hydroxysteroid levels). In addition, the latter specialist tests are not always feasible. There are two key benefits to a genetic diagnosis. Firstly, there is a clinical overlap between different syndromes of hypertension with hyperaldosteronism, and management of GRA and related hypokalaemic conditions is not identical, so a definitive diagnosis permits optimal therapy in each case. Secondly, genetic diagnosis avoids the expense of clinical assessment of at-risk relatives by experienced clinicians and the need for biochemical evaluation can be avoided. 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. 5
Referral Pathway Template NOTE: Please use this page as a template. Please expand the test boxes manually as needed. TARGET POPULATION (Description) Patients with a clinical diagnosis of GRA At risk relatives of patients with an identified mutation WHAT TYPE AND LEVEL OF PROFESSIONAL OR REFERRER DO YOU ACCEPT SAMPLES FROM? Consultant renal physicians, clinical pharmacologists or endocrinologists PLEASE PROVIDE DETAILS OF HOW REFERRALS WILL BE ASSESSED FOR APPROPRIATENESS? All referrals will be assessed by a locally based physician expert in the clinical diagnosis of GRA. For presumed affected individuals, biochemical evidence of primary hyperaldosteronism with either a dominant family history, or a family history of premature CVA or other supporting biochemical evidence will be required HOW MANY TESTS DO YOU EXPECT TO PERFORM ANNUALLY? 10 6
UKGTN Testing criteria for disease: Name of Disease(s): GLUCOCORTICOID-REMEDIABLE ALDOSTERONISM; GRA (103900) Name of gene(s): cytochrome P450, family 11, subfamily B, polypeptide 2; CYP11B2 (124080) cytochrome P450, family 11, subfamily B, polypeptide 1 ; CYP11B1 (610613) 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 Consultant Nephrologist Consultant Endocrinologist Consultant Clinical Pharmacologist Tick if this refers to you. Minimum criteria required for testing to be appropriate as stated in the Gene Dossier: Criteria Hypertension and Primary hyperaldosteronism AND > 2 of the following: 1) Dominant family history of hypertension 2) Family history of CVA under 60y 3) Urine18 hydroxysteroid excess 4) Positive steroid suppression test 5) On >3 drugs for hypertension 6) Hypokalemia (esp. if on thiazide) Or At risk relatives where a familial mutation has already 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. 7