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Proposal form for the evaluation of a genetic test for NHS Service Gene Dossier Test – Disease – Population Triad Disease – name TAR SYNDROME OMIM number for disease 274000 Disease – alternative names please provide any alternative names you wish listed CHROMOSOME 1q21.1 200KB DELETION SYNDROME, THROMBOCYTOPENIA-ABSENTRADIUSSYNDROME TETRAPHOCOMELIA-THROMBOCYTOPENIA SYNDROME, INCLUDED Disease – please provide a brief description of the disease characteristics Clinically well characterised malformation syndrome. Typical features include hypomegakaryocytic thrombocytopenia and bilateral absence of the radius in the presence of both thumbs. Additional skeletal features include shortening, and less commonly, aplasia of the ulna and/or humerus. Lower limb involvement present to a lesser extend. TAR is multiple malformation syndrome and extra skeletal manifestations comprise cardiac abnormalities such as tetralogy of Fallot, and abnormalities of the genitourinary tract. In addition cow’s mlk intolerance appears to be relatively common and may lead to eosinophilia. Genetic basis is currently unknown. 200kb deletion at 1q21.1 is necessary but not sufficient to cause the phenotype, additional modifying factors have been proposed. In approx 75% of cases the deletion is inherited from one parent, 25% cases are sporadic. 200kb deletion at 1q21.1 encompassing the genes;HFE2, TXNIP, PLOR3GL, ANKRD34A, LIX1L, RBM8A, GNRHR2, PEX11B, ITGA10, ANKRD35, PIAS3, NUDT1. This region is deleted in all patients. Klopocki et al 2007 report that 28/20 TAR syndrome individuals have a larger 500kb deletion extending towards the telomere including and additional 5 genes. Both TAR syndrome associated deletions are distinct and separate from the 1q21.1 deletion/duplication syndromes. Disease - mode of inheritance Gene – name(s) OMIM number for gene(s) Gene – alternative names please provide any alternative names you wish listed Klopocki E, Schulze H, Strauss G, Ott CE, Hall J, Trotier F, Fleischhauer S, Greenhalgh L, Newbury-Ecob RA, Neumann LM, Habenicht R, König R, Seemanova E, Megarbane A, Ropers HH, Ullmann R, Horn D, Mundlos S. Complex Inheritance Pattern Resembling Autosomal Recessive Inheritance Involving a Microdeletion in TAR syndrome. Am J Hum Genet. 2007; 80: 232–40. n/a n/a Gene – description(s) (including 200 kb deletion at 1q21.1 encompassing 11 genes. number of amplicons). 1 Approval Date: Sept 2010 Submitting laboratory: Bristol Genetics Laboratory Copyright UKGTN © 2010 Mutational spectrum for which you 200kb deletion at 1q21.1 test including details of known common mutations. 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? Multiplex Ligation dependant probe amplification ( MLPA ). This technique is currently employed at BGL for many routine diagnostic assays using commercial kits available form MRC Holland. An in-house MLPA was successfully developed in 2009 for Axenfeld Reigers syndrome using MRC-Holland p300-A1 probe mix. The 1q21.1 assay contains 3 probes mapping to the 200kb deleted region, flanking probes ( within the 500 kb deletion and also flanking this ) and control probes from other non-polymorphic regions of the genome. Routine statistical analysis is applied using GeneMarker software. This included the following steps: • design MLPA probes for use with the MRC-Holland p300A1 probe mix; • Check primers for SNPs using ‘primer3’ and ‘SNP check Manchester NGRL’ online software • Set-up the dosage analysis and optimise the MLPA assay using 5 ‘Normal controls’ commercially available from Health Protection Agency Culture Collections and 28 positive cases banked as extracted DNA at the laboratory please provide details ( collected at BGL as part of research study ) and confirmed as positive by qPCR testing at the research laboratory of Dr Stefan Mundlos and Dr Eva Klopocki in Berlin. No Validation of assay ongoing. There are 28 families referred for TAR syndrome testing stored at BGL. 20/28 have a confirmed If yes, how many reports have you deletion of 1q21.1 as tested by Dr E Klopocki by quantitative PCR produced? testing as a research study. In 6/28 families DNA was not Please give the number of mutation available from the index case. 2/28 families do not have the 1q positive/negative samples you have deletion, but other chromosome anomalies have been detected. reported The deletion is present one parent in 8/20 families. MLPA validation is underway at BGL on 28 positive DNA samples and normal controls. No laboratory diagnostic test yet available. 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 Yes Please provide details Dr Ruth Newbury-Ecob is a clinical geneticist with research expertise in this area. Previous collaborations include the Klopocki Am J Hum Genet 2007 TAR syndrome paper. Roberts syndrome (MIM268300) and Fanconi Anaemia (MIM 227650) UKGTN providers. ASD dossier in preparation. Ruth Newbury-Ecob is clinical expert in Holt-Oram Syndrome. None, test validation ongoing. Your Current Activity If applicable - How many tests do you currently provide annually in your laboratory? 2 Approval Date: Sept 2010 Submitting laboratory: Bristol Genetics Laboratory Copyright UKGTN © 2010 Your Capacity if Gene Dossier approved How many tests will you be able to provide annually in your laboratory if this gene dossier is approved and recommended for NHS funding? Index cases: Capacity will be available to meet demand for UK and abroad. Test is straightforward. Family members where mutation is known: Based on experience how many Index cases: UK cases 30 per annum tests will be required nationally (UK Family members where mutation is known 30 per annum wide)? Please identify the information on which this is based We are not aware of other labs providing this activity, we are able National Activity to provide for UK cases and abroad. (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 Estimated gene frequency (Carrier frequency or allele frequency) 0.42 cases per 100,000 live births in Spain. The prevalence of TAR syndrome is generally estimated at 0.5:100,000 to 1:100,000 No accurate data available. Please identify the information on which this is based Estimated penetrance Please identify the information on which this is based 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) Other unknown factors associated with expression of disease phenotype. 1. Diagnostic testing. Patients with a clinical diagnosis of TAR syndrome with bilateral absence of the radii with the presence of both thumbs and thrombocytopenia (<50 platelets/nL), generally transient. Molecular confirmation of diagnosis in pregancies where radial anomalies are identified on routine ultrasound. 3 Approval Date: Sept 2010 Submitting laboratory: Bristol Genetics Laboratory Copyright UKGTN © 2010 2. At risk testing. Unaffected parents of patients with a positive molecular diagnosis of TAR ( 75% cases are inherited ) to establish recurrence risks. Sibs and extended relatives of patients where patents are carrying the 200kb deletion. Offspring of a patient with a molecular diagnosis of TAR syndrome. 3. Prenatal testing. Prenatal diagnosis for pregancies at increased risk of TAR syndrome, coupled with ultrasound evaluation of fetal limbs and heart. Estimated prevalence of disease in the target population 100% of patients with TAR syndromes have the 200kb deletion at 1q21.1. 75% cases this will be carried by one parent who will be unaffected although radiographs of the limbs are recommended as minor limb involvement in some has been reported. Risk of inheriting the deletion is 50%, prenatal diagnosis must be accompanied by ultrasound examination to evaluate the limbs, as the deletion alone is not sufficient for the diagnosis of TAR syndrome. 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 √ NO Presymptomatic testing Risk Assessment for family members √ Risk Assessment – prenatal testing √ 4 Approval Date: Sept 2010 Submitting laboratory: Bristol Genetics Laboratory Copyright UKGTN © 2010 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. Validated MLPA will be 100% sensitive for detecting the 200kb deletion event. It will not inform over the extent of the deletion beyond this region, but that is not currently considered clinically relevant. Clinical sensitivity and specificity of test in target population Klopocki et al Am J Hum Genet 2007 80 232-240 indicate that 30/30 unrelated TAR affected individuals have this 200kb deletion at 1q21.1. Clinical sensitivity 100%. This deletion is sufficient to confirm the diagnosis in individuals with bilateral absence of the radius and presence of thumbs. 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 validity (positive and negative predictive value in the target population) 75% cases are inherited from an unaffected parent indication that haploinsufficiency is not sufficient for the phenotype and a second unknown mutant gene is required. Family testing can identify those at risk. This should be supported by ultrasound examination to evaluate limbs in prenatal diagnosis, and radiographs of limbs should be considered in parents/relatives carrying the deletion as minor limb involvement in some has been reported. Negative predictive value 100%. In the presence of symptoms positive predictive value 100%. 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). 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. Family testing required ultrasound/radiograph support, but identified those at risk. Diagnostic/exclusion/family/prenatal tests for 1q21.1 deletion only. 5 Approval Date: Sept 2010 Submitting laboratory: Bristol Genetics Laboratory Copyright UKGTN © 2010 Clinical utility of test in target population (Please refer to Appendix A) Molecular confirmation of a clinical diagnosis provided definitive diagnosis and facilitates family testing allowing the identification of at risk relatives, recurrence risks and prenatal diagnosis. This is particularly important as many carrier parents are asymptomatic. Provides reassurance to those who do not carry the deletion. Please provide a description of the Prenatal diagnosis is possible with confirmation by ultrasound. clinical care pathway. How will the test add to the management of the patient or alter clinical outcome? Confirmation of diagnosis will inform on patient prognosis and aid in patient management and treatment. Allows monitoring and treatment to be performed sooner e.g. platelet transfusion for thrombocytopenia, platelet count surveillance. Enables determination of recurrent risk for future pregnancies. High risk where one parent carries deletion. Very low if neither parent carries deletion. 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. Early targeting and management. Defining those at risk. Treatment as above. What are the consequences of not doing this genetic test. Commissioners have asked for specific information to support introduction of tests. Those at risk of having TAR syndrome affected offspring will not be identified or appropriately supported. Babies could be born with a severe disability. Incorrect diagnosis with incorrect genetic information Utility of test in the NHS In a couple of sentences explain the utility of this test for the disease(s) Definitive diagnosis supporting early monitoring, treatment and orthopaedic intervention. Identification of those at risk and reassurance to those not at risk. Prenatal diagnosis made possible. 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 alternative test available. Ultrasound and radiography is not specific. Deletion can be detected as part of aCGH screen but this is a nonspecific test Please describe any specific ethical, legal or social issues with this particular test? Patients with TAR have long term health care needs. Accurate diagnosis will contribute to good clinical management and appropriate educational support in the case of children. 6 Approval Date: Sept 2010 Submitting laboratory: Bristol Genetics Laboratory Copyright UKGTN © 2010 UKGTN Testing criteria Name of Disease(s): CHROMOSOME 1q21.1 DELETION SYNDROME, 200-KB (274000) Name of gene(s): 200kb deletion 1q21.1 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 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 Bilateral absence of the radii with the presence of both thumbs and thrombocytopenia (<50 platelets/nL) OR radial anomalies identified on a routine ultrasound evaluation with thumbs present Family testing for parents of cases with molecular confirmation of diagnosis, and testing of relatives where parents are carrying the 200kb deletion Prenatal diagnosis for pregnancies at increased risk in combination with ultrasound evaluation of limbs. 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 Approval Date: Sept 2010 Submitting laboratory: Bristol Genetics Laboratory Copyright UKGTN © 2010