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 OMIM number for disease Gene name and description (please provide any alternative names you wish listed) OMIM number for Gene X-Linked VACTERL with Hydrocephalus Syndrome Fanconi Anaemia Complementation Group B Males affected with Hydrocephalus and features of the VACTERL association Fanconi Anaemia Complementation Group B (FANCB) Mutational spectrum for which you test Technical Method (s) 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? Deletions and point mutations Bi-directional DNA sequencing To determine that this method can accurately detect mutations, DNA samples from affected males with FANCB mutations that had been analysed in a research lab were tested. The mutations were confirmed, and the mother from one of these individuals was shown to be a carrier. A previously unreported point mutation and a deletion of exons 8-10 were identified in two further patients with X-linked VACTERL hydrocephalus syndrome sent to our laboratory for analysis during the development of this test. No 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? N/A Yes Please provide details Dr Simon Holden clinical expertise Ian Kesterton cytogenetics diagnostic testing for Fanconi Anaemia (FA) (chromosome breakage using DNA cross-linking agents) Autosomal recessive FA (see above) 3-6 full diagnostic tests plus 3-6 carrier tests. 1

2 Based on experience how many tests will be required nationally (UK)? Please identify the information on which this is based 3-6 full diagnostic tests plus 3-6 carrier tests Referrals to this department in the last 2 years (national and international) 2

3 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) Approximately less than 1 per million of the population. FANCB is thought to represent approximately 1% of all cases of Fanconi Anaemia, the total carrier frequency of the recessive forms being estimated at 1 in 300. To date, only 5 cases have been reported in the medical literature. Many cases are lethal in utero. Approximately 1 per million Please identify the information on which this is based Estimated penetrance Please identify the information on which this is based Target Population The essential clinical or family history features defining the target population must be described. (C)-Testing Criteria 100% in males. This is based on the gene being X-linked and the observed severity of the phenotype in those affected males with reported mutations. Female carriers do not appear to manifest physical signs of the condition. Studies have shown that affected females have completely skewed X-inactivation in multiple tissues with different embryological origins, suggesting strong selection against cells expressing the mutant allele during early embryogenesis. Males with hydrocephalus and features of the VACTERL association. Clinical manifestations include Hydrocephalus and bilateral thumb and/or radial defects. Other common manifestations include renal and genital abnormalities, vertebral defects, congenital heart disease and tracheo-oesophageal fistulas, atresias of the gastrointestinal tract, abnormal ears and cleft palate. Affected males have abnormal chromosome breakage when exposed to DNA cross-linking agents such as diepoxybutane (cytogenetic diagnostic test for FA). Carrier females have completely skewed X-inactivation in peripheral blood. An X-linked family history is strongly suggestive of a FANCB mutation. However, as the phenotype has been associated with autosomal recessive cases of FA, all affected males with hydrocephalus and features of VACTERL association should be considered for FANCB mutation testing. Testing criteria: Males with: Hydrocephalus and Bilateral thumb or radial abnormalities And one of the following: Abnormal chromosome breakage/sensitivity to DNA crosslinking agents Vertebral defects Renal abnormalities Genital abnormalities Gastrointestinal atresia Tracheo-oesophageal atresia Congenital heart disease 3

4 Estimated prevalence of disease in the target population Approximately 1 per million pregnancies. Due to the high intrauterine mortality associated with this condition, the prevalence in male infants and children is lower. No surviving adult males with FANCB mutations have been reported. 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 Yes Yes Yes NO No No 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. Bi-directional sequencing coupled with Mutation Surveyor software has a quoted sensitivity and specificity of >99%. 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) The VACTERL with hydrocephalus phenotype is observed in autosomal recessive causes of FA in addition to those cases with FANCB mutations. Due to this heterogeneity, clinical sensitivity and specificity of the FANCB mutation screen are difficult to estimate. These will also be influenced by the quality of the clinical referral. 5

6 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 The VACTERL with hydrocephalus phenotype associated with FANCB mutations appears to be fully penetrant in affected males. Carrier females do not manifest clinical features of the phenotype. For male fetuses with FANCB mutations detected in utero, the positive predictive value is predicted to be = 1. The sensitivity and specificity of this test in all known cases affected with the VACTERL with hydrocephalus phenotype are unknown. Negative predictive value is therefore difficult to calculate. 6

7 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 Affected individuals with VACTERL and hydrocephalus phenotype will have blood sample taken for both FANCB mutation screening and cytogenetic chromosome breakage analysis. Mothers of affected individuals will have blood sample taken for both FANCB mutation screening and X-inactivation analysis. Referrals will be received from Clinical Geneticists. Testing criteria: Males with: Hydrocephalus and Bilateral thumb or radial abnormalities 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? And one of the following: Abnormal chromosome breakage/sensitivity to DNA crosslinking agents Vertebral defects Renal abnormalities Genital abnormalities Gastrointestinal atresia Tracheo-oesophageal atresia Congenital heart disease The majority of affected fetuses have severe phenotypes and may die in utero. Only 5 known males survived and all are <4 years of age. Long term natural history is not known, but the severity is predicted to be similar to autosomal forms of FA. This information can be used by a family to make lifestyle choices including prenatal diagnosis. 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 This test will confirm the FA is X-linked which will impact only on female relatives of a carrier mother. An alternative means of diagnosis would be by cytogenetic analysis using chromosome breakage but this does not distinguish between X-linked and autosomal recessive forms of FA. There are no specific ethical, legal of social issues with this test. Are there specific ethical, legal or social issues with this test? Please complete the referral pathway diagram on the following page and the testing criteria form. 7

8 Referral Pathway Template NOTE: Please use this page as a template. Please expand the test boxes manually as needed. TARGET POPULATION (Description) Males with VACTERL with Hydrocephalus phenotype Males with chromosome breakage identified by cytogenetic analysis Females with family history of X-linked VACTERL with Hydrocephalus Syndrome WHAT TYPE AND LEVEL OF PROFESSIONAL OR REFERRER DO YOU ACCEPT SAMPLES FROM? Clinical Geneticists 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? 3-6 full diagnostic tests plus 3-6 carrier tests 8

9 UKGTN Testing criteria: Name of Disease(s): VACTERL ASSOCIATION WITH HYDROCEPHALUS, X-LINKED (314390) Name of gene(s): Fanconi anemia, complementation group B; FANCB (300515) 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 Geneticists Tick if this refers to you. Minimum criteria required for testing to be appropriate as stated in the Gene Dossier: Criteria Males with: Hydrocephalus AND Bilateral thumb or radial abnormalities AND one of the following: Abnormal chromosome breakage/ sensitivity to DNA cross-linking agents Vertebral defects Renal abnormalities Genital abnormalities Gastrointestinal atresia Tracheo-oesophageal atresia Congenital heart disease X-linked family history Tick if this patient meets criteria Family history of X-linked VACTERL with Hydrocephalus Syndrome & known mutation 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. 9