Proposal form for the evaluation of a genetic test for NHS Service Gene Dossier

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1 Proposal form for the evaluation of a genetic test for NHS Service Gene Dossier Test Disease Population Triad Disease name Loeys-Dietz Syndrome OMIM number for disease ; ; ; Disease alternative names please provide any alternative names you wish listed Disease please provide a brief description of the disease characteristics Disease - mode of inheritance Familial thoracic aortic aneurysm 3 (AAT3) Familial thoracic aortic aneurysm 5 (AAT5) Furlong Syndrome Loeys-Dietz aortic aneurysm syndrome Thoracic aortic aneurysm and dissection Loeys-Dietz Syndrome is an autosomal dominant aortic aneurysm syndrome with widespread systemic involvement and variable clinical expression. The disorder is characterised by arterial tortuosity and aneurysms, hypertelorism and bifid uvula or cleft palate. Patients are assigned to the type 1 category if craniofacial involvement consisting of cleft palate, craniosynostosis or hypertelorism is observed. Patients in the type 2 category have none of these findings, although some may have a bifid uvula. Other features include marfanoid body habitus and translucent skin. Autosomal dominant Gene name(s) Transforming growth factor beta receptor 1 Transforming growth factor beta receptor 2 OMIM number for gene(s) Gene alternative names please provide any alternative names you wish listed Gene description(s) (including number of amplicons). Mutational spectrum for which you test including details of known common mutations. Technical Method (s) ALK5 (TGFBR1) HNPCC6 (TGFBR2) TGFBR1 - Locus 9q22. The longest transcript consists of 9 exons (9 amplicons) and 504 amino acids TGFBR2 - Locus 3p22. The longest transcript consists of 8 exons (numbered 1, 1a to 7 in the literature) and 593 amino acids. Exon 4 is amplified in 3 overlapping fragments and there are 10 amplicons in total. Missense, nonsense and small insertion and deletion mutations. No common mutations known. Bidirectional fluorescent DNA sequencing Validation Process Note: please explain how this test has been validated for use in your laboratory DNA sequencing is a standard analytical method used in the laboratory for a range of diagnostic services requiring mutation detection. The laboratory participates in external quality assessment for sequence analysis. All primers used are regularly checked for single nucleotide polymorphisms (SNPs). 1

2 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? Are you testing for other genes/diseases closely allied to this one? Please give details Your Current Activity If applicable - How many tests do you currently provide annually in your laboratory? Your Capacity if Gene Dossier approved How many tests will you be able to provide annually in your laboratory? No If Yes: Number of reports issued: Number of reports mutation positive: Number of reports mutation negative: New service Yes Please provide details Dr Angela Barnicoat (Consultant Clinical Geneticist) and Dr. Ajith Kumar (Consultant Clinical Geneticist). Patients are currently seen in general genetics clinics. Plans are in place to develop the cardiac genetics service in co-operation with cardiologists in the London Heart Hospital, London Chest Hospital and the Essex Cardiothoracic Centre. No Although no testing is currently carried out in our laboratory, the local clinical genetics department currently see patients per year. This number is expected to increase with the introduction of cardiac genetics clinics. Index cases: 50 Family members where mutation is known: 150 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) Please identify the information on which this is based Estimated penetrance Please identify the information on which this is based Rare: Less than 1/100,000 Rare: Less than 1/100,000 The penetrance is approaching 100% for TGFBR1. There have been rare proposed cases of incomplete penetrance for TGFBR2 although the pathogenicity of these variants may not be certain. (Stheneur et al, Hum. Mut, 29: E284-E295) 2008 (online) ; Matyas et al, Hum. Mut. 27(8) : (2006)) There is one proven case of somatic mosaicism in the father of a child with LSD (Watanabe et al Am J Med Genet 146A(23): (2008). 2

3 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) Estimated prevalence of disease in the target population Patients that are clinically affected for confirmation of diagnosis and to assess recurrence risk in their family. Minimal diagnostic criteria for Loeys Dietz syndrome have not been established but patients are expected to have at least two of the following features: - Dilatation of the aortic root/ aortic dissection - Tortuosity or aneurysm of other arteries - Marfanoid body habitus - Craniofacial features such as craniosynostosis, hypertelorism, cleft palate or bifid uvula - Translucent skin 95% Confirmed Loeys-Dietz patients have a mutation in TGFBR1 or TGFBR2 Intended Use (Please use the questions in Annex A to inform your answers) Please tick the relevant clinical purpose of testing YES NO Diagnosis Treatment Prognosis & Management Presymptomatic testing Risk Assessment for family members Risk Assessment prenatal testing 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. Direct DNA sequencing has a high sensitivity in this laboratory. We use Big Dye chemistry, ABI analysers (3100, 3130XL, 3730) and analyse using Mutation Surveyor software. The laboratory also participates in all relevant technical EQA schemes that are available through UK NEQAS and EMQN: Genotypes correctly assigned in 3/3 sequencing EQA samples Genotypes correctly assigned in 3/3 sequencing EQA samples Genotypes correctly assigned in 3/3 sequencing EQA samples Genotypes correctly assigned in 4/4 sequencing EQA samples. Bidirectional sequence analysis has specificity approaching 100% although large insertions / deletions and deep intronic mutations will not be detected. No such mutations have been reported so far in the literature for TGFBR1 and TGFBR2. 3

4 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 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). 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. Clinical utility of test in target population (Please refer to Appendix A) Please provide a description of the clinical care pathway. The clinical sensitivity for sequencing both TGFBR1 and TGFBR2 has been reported as 95% for Loeys-Dietz syndrome. Loeys et al; N Engl J Med Aug 24;355(8): Given the aggressive course of the disease specificity is also expected to be high. Mutations in TGFBR2 are responsible for a continuum of phenotypes from severe LDS to milder familial thoracic aortic aneurysm and dissection (TAAD), which is an adult-onset disease with no syndromic features. Variants of uncertain pathogenicity may be identified during testing of affected or unaffected individuals. The positive predictive value is high in the target population of patients clinically affected with Loeys-Dietz syndrome. Marfan and Marfan-like patients have a reported low yield of TGFBR1 and TGFBR2 mutations. Stheneur et al, Hum. Mut, 29: E284-E295) 2008 (online) The negative predictive value is also high although patients with dilatation of the aortic root/ aortic dissection and Marfanoid body habitus should also be evaluated for Marfan syndrome caused by FBN1 mutations. TGFBR1 and TGFBR2 will be tested simultaneously using robotic sample handling. Onset of the disease can be from early childhood, the mean age of fatal aortic dissection in one series was mid 20s. Confirmation of the diagnosis is therefore vital given the aggressive course of the disease and is required for appropriate management of confirmed cases and reassurance of non-carriers in the family. Testing also allows clinicians to distinguish between Loeys-Dietz (TGFBR1/2) and conditions with a similar differential diagnosis e.g. Marfan syndrome and other connective tissue disorders. 4

5 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? Please provide evidence from your own service. What are the consequences of not doing this genetic test. Commissioners have asked for specific information to support introduction of tests. Utility of test in the NHS In a couple of sentences explain the utility of this test for the disease(s) 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 Please describe any specific ethical, legal or social issues with this particular test? Diagnosis of Loeys-Dietz syndrome is important, as affected individuals benefit from frequent echocardiography and extensive vascular imaging (up to 50% of LDS patients have an aneurysm not detectable by echocardiography) to monitor the size of the ascending aorta and lifestyle issues such as sport / exercise can be considered. Affected patients have a high risk of aortic dissection or rupture at an early age at diameters which would not ordinarily predict these events. Surgical intervention in LDS patients is generally successful providing the surgical team is appraised of the diagnosis and potential complications. Close medical management of pregnancies is essential. Identification of a molecular cause for a patient s condition avoids further molecular investigations for diseases with a similar differential diagnosis (some of which are costly e.g. FBN1 for Marfan). ECG screening is not required for family members shown not to carry the mutation segregating in their family. MRA screening of at risk relatives can be avoided by presymptomatic genetic testing. Medical follow up can be offered to those who have a positive genetic test. Death through unpredicted aortic dissection. Lack of clarity on the cause of a patient s condition and subsequent evaluation of recurrence risk. Identification of gene-positive relatives in time to anticipate symptoms and prevent death through surveillance and surgical treatment. Non-carriers can be reassured and no longer require screening. The only alternative means of diagnosis is on clinical features alone. This would involve magnetic resonance angiography (MRA) or CT scans with 3D reconstruction from head to pelvis. N/A 5

6 UKGTN Testing criteria Name of Disease(s): LOEYS-DIETZ SYNDROME, TYPE 1A; LDS1A (609192) LOEYS-DIETZ SYNDROME, TYPE 2A; LDS2A (608967) LOEYS-DIETZ SYNDROME, TYPE 2B; LDS2B (610380) LOEYS-DIETZ SYNDROME, TYPE 1B; LDS1B (610168) Name of gene(s): transforming growth factor, beta receptor 1; TGFBR1 (190181) transforming growth factor, beta receptor II (70/80kDa); TGFBR2 (190182) 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 Geneticist Consultant Cardiologist 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 A patient should show at least two of the following features: Dilatation of the aortic root/aortic dissection Tortuosity or aneurysm of other arteries Marfanoid body habitus Craniofacial features such as craniosynostosis, hypertelorism, cleft palate/bifid uvula Translucent skin Notes: 1. Minimal diagnostic criteria for Loeys Dietz syndrome have not been established. 2. All patients with dilatation of the aortic root/aortic dissection and Marfanoid body habitus should be evaluated for Marfan syndrome. 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. 6