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 and description (please provide any alternative names you wish listed) (A)-Testing Criteria Hidrotic ectodermal dysplasia Clouston syndrome In contrast to X-linked hypohidrotic ectodermal dysplasia (305100), patients with dominantly inherited hidrotic ectodermal dysplasia have normal sweat and sebaceous gland function, total alopecia, severe dystrophy of the nails, hyperpigmentation of the skin, especially over the joints, and normal teeth. Strabismus, mental deficiency, clubbing of the fingers and palmar hyperkeratosis may occur. OMIM number for disease Gene name and description (please provide any alternative names you wish listed) OMIM number for Gene GJB6; Connexin 30 Mutational spectrum for which you Frameshift and missense mutations test Technical Method (s) Bi-directional sequencing of the single coding exon (2 PCR fragments) 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? This test is not currently in use in the regional diagnostic laboratory. The primer sets used have been SNP-checked, validated to ensure that the full coding sequence was covered, and optimised to work robustly under diagnostic conditions. Yes 1 report issued, mutation negative Yes Please provide details Prof. Angus Clarke, Consultant Clinical Geneticist who has a long standing research interest in EDA. 1

2 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)? /305100: EDA1 gene / X-linked anhidrotic ectodermal dysplasia EDAR gene / autosomal dominant and recessive anhidrotic ectodermal dysplasia Approx. 6 Approx. 6 Please identify the information on which this is based 2

3 Epidemiology Estimated prevalence of disease in the general UK population Significantly less than 1 per 100,000 Please identify the information on which this is based Estimated gene frequency (Carrier frequency or allele frequency) 1 per 100,000 is the incidence of all ectodermal dysplasias (and of XHED in males) Unknown Please identify the information on which this is based Estimated penetrance Please identify the information on which this is based >95% Target Population The essential clinical or family history features defining the target population must be described. Features of ectodermal dysplasia affecting hair, nails and skin but not teeth or sweating: hypotrichosis, dysplastic nails, hyperpigmentation of the skin, palmoplantar keratoderma. (C)-Testing Criteria Estimated prevalence of disease in the target population >90% 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 Y YES Risk Assessment Y (not prenatal) Y Y N NO 3

4 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. >95% (sequencing based assay) 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) Clinical sensitivity >95% All confirmed cases of HED to date have had one of three missense mutations in exon 3 of GJB6. Specificity >99% 4

5 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 A positive test result indicates confirmation of diagnosis. A negative result makes an alternative diagnosis highly likely. The penetrance is high; after infancy, an apparently unaffected individual is likely not to have inherited the disorder. 5

6 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. A patient with clinical features of hidrotic ED likely to be accounted for by mutations in this gene will usually present to a dermatologist or a clinical geneticist. There can be some diagnostic difficulty distinguishing between Clouston s ED and some types of pachyonychia congenita; mutation testing may help in these cases. A child at risk of inheriting the condition but apparently unaffected may present to a paediatrician. Referrals from other specialists would warrant enquiry as to the grounds for testing. (B)-Testing Criteria Criteria: at least three of these four: Sparse scalp hair Dysplastic nails Normal teeth and sweating Palmoplantar keratodermia and/or pigmented areas of skin How will the test add to the management of the patient or alter clinical outcome? Confirmation of diagnosis and mode of inheritance. 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? Remove need for skin biopsy or mutation searching in other loci (eg keratin genes). 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 No Are there specific ethical, legal or social issues with this test? No 6

7 Referral Pathway Template NOTE: Please use this page as a template. Please expand the test boxes manually as needed. TARGET POPULATION Patients must have three of four of the following criteria. ie. 1 & 2, & (3 or 4) 1. sparse scalp hair AND 2. dystrophic nails AND 3. normal teeth, sweating OR 4. palmoplantar keratoderma OR pigmented areas of skin WHAT TYPE AND LEVEL OF PROFESSIONAL OR REFERRER DO YOU ACCEPT SAMPLES FROM? A: Consultant clinical geneticist B: Consultant dermatologist PLEASE PROVIDE DETAILS OF HOW REFERRALS WILL BE ASSESSED FOR APPROPRIATENESS? (please complete the test criteria template on the following page) HOW MANY TESTS DO YOU EXPECT TO PERFORM ANNUALLY? Approx. 6 7

8 UKGTN Testing criteria: Name of Disease(s): ECTODERMAL DYSPLASIA 2, HIDROTIC; ED2 (129500) Name of gene(s): gap junction protein, beta 6, 30kDa; GJB6 (604418) 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 clinical Geneticists Consultant Dermatologists Tick if this refers to you. Minimum criteria required for testing to be appropriate as stated in the Gene Dossier: Criteria Criteria 1 and 2 must be present PLUS either 3 or 4: 1. sparse scalp hair AND 2. dystrophic nails AND 3. normal teeth, sweating OR 4. palmoplantar keratoderma or pigmented areas of skin 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