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) (A)-Testing Criteria Thyroid Hormone Resistance. Patients usually present following routine thyroid function testing with high serum free thyroine with paradoically non-suppressed TSH. Patients can be asymptomatic, have mild hyperthyroid features or attention deficit hyperactivity disorder in childhood. However they may be inappropriately treated if the syndrome is not recognised. The diagnosis can be confounded by analytical errors in the biochemical test, so the DNA test can confirm the diagnosis. OMIM number for disease 145650 Gene name and description (please provide any alternative names you wish listed) OMIM number for Gene Mutational spectrum for which you test Technical Method (s) Validation Process Autosomal dominant mode of inheritance THYROID HORMONE RECEPTOR, BETA; THRB 190160 Coding region and splice sites for eons 7-10 in THRB DNA sequencing THRbeta Note please eplain 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 250 samples with abnormal serum thyroid function tests have been analysed, with 175 mutations described. Reports from the literature have not detected mutations in other THRb eons 250 175 For how long have you been providing this service? 5 years 1
Is there specialised local clinical/research epertise 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 eperience how many tests will be required nationally (UK)? Yes X Please provide details Prof VK Chatterjee is international epert in this field Yes, familial dysalbuminaemic hypethyroinaemia can give a similar biochemical phenotype 50 50 Previous workload Please identify the information on which this is based 2
Epidemiology Estimated prevalence of disease in the general UK population Please identify the information on which this is based THRb 1:40000 Refetoff S, Dumitrescu AM. Syndromes of reduced sensitivity to thyroid hormone: genetic defects in hormone receptors, cell transporters and deiodination. Best Pract Res Clin Endocrinol Metab. 2007 Jun;21(2):277-305. Review Estimated gene frequency (Carrier frequency or allele frequency) THRb 1:80000 Based on disease prevalence Please identify the information on which this is based Estimated penetrance Please identify the information on which this is based To date we have not seen thyroid hormone levels within the local reference ranges in mutation positive patients Target Population The essential clinical or family history features defining the target population must be described. Patients with raised serum free thyroine with inappropriately non-supressed serum thyrotropin (C)-Testing Criteria Estimated prevalence of disease in the target population 70% Intended Use (Please use the questions in Anne A to inform your answers) Please tick the relevant clinical purpose of testing Diagnosis Treatment Prognosis & Management Presymptomatic testing YES NO Risk Assessment 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. Bi-directional sequencing coupled with Mutation Surveyor software has a quoted sensitivity of >99% and specificity of >99% If a number of genes will be tested, please include your testing strategy and data on the epected 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) Specificity 100% Sensitivity 70% 4
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 This test will be used in patients with abnormal thyroid function tests. Consequently identifying a mutation will have a positive predictive value of 100%. As the test will not be used in patients with normal thyroid function tests (apart from family screening) negative predictive value is not relevant. 5
Clinical utility of test in target population (Please refer to Appendi 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? 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? Serum Thyroid function testing is widely undertaken in primary care due to the non-specific nature of thyroid disease. Patients with thyroid hormone resistance will present with raised free thyroine and inappropriately non-suppressed TSH. However biochemical assay related problems can give a similar picture. There is a real danger that these patients will be inappropriately treated for hyperthyroidism. At this stage a chemical pathologist may suspect the syndrome, or the patient may be referred to an endocrinologist, who may also suspect the syndrome. Either of these professions may instigate the testing strategy for thyroid hormone resistance. As assay problems are more prevalent than thyroid hormone resistance, attempts to eclude analytical error should proceed at this stage. However there is no good method to completely eclude assay problems, particularly as the gold standard method (equilibrium dialysis T4) is no longer available in the UK. A positive gene test at this stage effectively validates the biochemical results. The purpose of the test is to avoid inappropriate treatment for hyperthyroidism in the inde case, and in family members as appropriate. As thyroid function testing is so common, family members have a reasonable a priori chance of having a thyroid function test during their lifetime (appro 1/3 in East Anglia), so an awareness of the condition is likely to be beneficial The test provides a positive diagnosis, and can prevent further costly or inappropriately invasive tests or treatments for thyroid disease. 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 The condition can be diagnosed by autosomal dominant transmission of characteristic thyroid function tests, provided these data are available from sufficient family members, and these are easily obtainable. Are there specific ethical, legal or social issues with this test? An endocrinologist that misses this diagnosis and mistreats a patient with thyroid hormone resistance may be liable for litigation Please complete the referral pathway diagram on the following page and the testing criteria form. 6
Referral Pathway Template NOTE: Please use this page as a template. Please epand the test boes manually as needed. TARGET POPULATION Patients with raised serum thyroid hormones with inappropriately non-suppressed thyrotropin, detected during thyroid function testing, after attempts to eclude assay interference as a cause of the biochemical results. Relatives of gene test positive patients with thyroid hormone resistance. WHAT TYPE AND LEVEL OF PROFESSIONAL OR REFERRER DO YOU ACCEPT SAMPLES FROM? Consultant endocrinologist, Chemical pathologist or geneticist PLEASE PROVIDE DETAILS OF HOW REFERRALS WILL BE ASSESSED FOR APPROPRIATENESS? Attempts to eclude assay interference in the thyroid function tests will have been made, either by the requestor or locally upon provision of a serum sample of at least 2 ml. HOW MANY TESTS DO YOU EXPECT TO PERFORM ANNUALLY? 50 7
UKGTN Testing criteria for disease: Name of Disease(s): THYROID HORMONE RESISTANCE, SELECTIVE PITUITARY; PRTH (145650) Name of gene(s): Thyroid Hormone Resistance / thyroid hormone receptor, beta (erythroblastic leukemia viral (v-erb-a) oncogene homolog 2, avian); THRB (190160) 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 Geneticist Consultant Endocrinologist Consultant Chemical Pathologist Tick if this refers to you. Minimum criteria required for testing to be appropriate as stated in the Gene Dossier: Criteria Relative of gene test positive patient OR Raised serum ft4 or ft3 with inappropriately non-suppressed serum TSH AND Attempts to eclude Assay interference or provision of at least 2 ml of serum. 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. 8