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

Transcription

1 Proposal form for the evaluation of a genetic test for NHS Service Gene Dossier/Additional Provider TEST DISORDER/CONDITION POPULATION TRIAD Submitting laboratory: Bristol RGC Approved: Sept Disorder/condition approved name and Arthrogryposis, Distal, Type 1A; DA1A symbol as published on the OMIM Arthrogryposis, Distal, Type 2B; DA2B (Sheldon-Hall database (alternative names will be listed on the syndrome) UKGTN website) 2. OMIM number for disorder/condition Arthrogryposis, Distal, Type 1A; DA1A Arthrogryposis, Distal, Type 2B; DA2B 3a. Disorder/condition please provide, in Distal Arthrogryposis (DA) is a group of disorders laymen s terms, a brief (2-5 sentences) characterised by congenital contractures in the distal description of how the disorder(s) affect limbs without an obvious neurogenic or myopathic individuals and prognosis. cause. Ten different clinical forms (DA1 to DA10) have been described, with DA1 and DA2B as the most common forms and some other very rare forms. Features shared amongst all distal arthrogryposes include consistent patterns of hand and foot involvement, limited involvement of proximal joints, and variable expressivity within families. Patients usually have a normal lifespan, some become completely independent, others continue to require assistance. Limitations are mainly regarding pain and muscle fatigue, but in some cases also have quite severe limitations of joint mobility. Many patients are required to undergo repeated surgical intervention. 3b Disorder/condition if required please expand on the description of the disorder provided in answer to Q3a. DA1 is characterised by camptodactyly and talipes, but the shoulders and hips may sometimes be affected. Hypoplasia is common. The degree to which the joints are affected is highly variable. DA2B (Sheldon-Hall Syndrome) is a relatively mild form of arthrogryposis which is characterised by small mouth, facial contractures, scoliosis, mainly distal contractures and short stature. Mutations in genes encoding sarcomeric muscle proteins are found in several DA syndromes. Mutations in TPM2 and MYBPC1 (*160794) have been described in patients with DA1. Mutations in TPM2, TNNI2 (*191043), TNNT3 (*600692) and MYH3 (*160720) cause DA2B. 4. Disorder/condition mode of inheritance Autosomal Dominant and de novo 5. Gene approved name(s) and symbol as tropomyosin 2 (beta); TPM2 published on HGNC database (alternative names will be listed on the UKGTN website) 6a. OMIM number for gene(s) b HGNC number for gene(s) HGNC: a. Gene description(s) TPM2, chromosome location 9p13.3. The TPM2 gene encodes beta-tropomyosin, an isoform of tropomyosin that is mainly expressed in slow, type 1 muscle fibers.

2 7b. Number of amplicons to provide this test (molecular) or type of test (cytogenetic) 7c. GenU band that this test is assigned to for index case testing 8. Mutational spectrum for which you test including details of known common mutations There are two isoforms: The skeletal muscle isoform and the fibroblast isoform in which alternative splicing of exons 6 & 9 occur. Mutations have been described in the skeletal muscle isoform cdna 1189bp, amino acids 284, 9 exons. Tropomyosin is a member of the actin filament binding protein family (in muscle and non-muscle cells) and part of a multimeric complex of the sarcomere (along with actin, troponins C, I, T and myosin) (Tajsharghi H et al 2008 Arch Neurol 65(8); ); mutations appear to affect myofibre contractility (Bamshad M et al 2009 J Bone Joint Surg Am. 91 Suppl 4:40-6), Mutations in the TPM2 gene also cause Nemaline Myopathy (#609285), Cap Disease (#609285), and as yet unspecified congenital myopathy. Tajshargi H et al (2012) Neuromsucular Disorders 22: amplicons, including coverage of alternative exons 6 & 9. GenU band E Sanger sequence analysis of the entire coding regions of genes, splice sites and branch points for point mutations and small insertions and deletions. Human Gene Mutation Database (HGMD) indicates that 10 (14 in HGMD professional) TPM2 mutations have been detected so far including substitution and small insertion/deletion mutations. Only 1 mutation on this database is associated with DA (the others are associated with nemaline myopathy and muscle weakness and distal limb deformity). 100% reported TPM2 mutations are detectable by sequencing. The Leiden Muscular Dystrophy database ( lists 32 unique TPM2 variants to date; 6 mutations are associated with DA (3 missense mutations and 3 possibly affecting splicing) which would be detected by sequencing. 9a. Technical method(s) High Throughput (HT) Automated sequence analysis. Gene screening by bidirectional automated HT sequence analysis (Beckman NX/ABI3730), the standard platform used for gene screening at BGL and analysis of the results with Mutation Surveyor software. 9b If a panel test using NGS please state if it is a conventional panel or a targeted exome test. 9c. Panel/targeted exome Tests i) Do the genes have 100% coverage? If not what is the strategy for dealing with the gaps in coverage? ii) Does the test include MLPA? iii) Does this use sanger sequencing or Next Generation Sequencing (NGS)? Section not applicable

3 iv) If NGS is used, does the lab adhere to the Practice Guidelines for NGS? 10 Is the assay to be provided by the lab or is it to be outsourced to another provider? If to be outsourced, please provide the name of the laboratory. 11. Validation process Please explain how this test has been validated for use in your laboratory or submit your internal validation documentation Assay to be provided by Bristol Genetics Laboratory HT automated sequence analysis: This method is routinely used to screen for mutations at BGL and had been validated for many services. Beckman NX robotics /ABI 3730 capillary electrophoresis and mutation surveyor software analysis are routinely used in the laboratory. Positive and negative control samples are included. Primers (SNP checked) have been designed to cover the coding regions and intron-exon boundaries. BGL also participates in external quality assurance EMQN sequencing QA schemes (since the pilot scheme was introduced in 2002). 12a. Are you providing this test already? No The assay has been validated on known normal controls stored in the laboratory. We do not have access to DNA from patients tested in research laboratories to use as positive controls for validation purposes. 12b. If yes, how many reports have you produced? Please provide the time period in which these reports have been produced and whether in a research or a full clinical diagnostic setting. 12c. Number of reports mutation positive 12d. Number of reports mutation negative 13. For how long have you been providing this service? 14a. Is there specialised local clinical/research expertise for this disorder? Yes 14b. If yes, please provide details Dr Sarah Smithson, Consultant in Clinical Genetics, St Michael s Hospital, Bristol 15. Are you testing for other genes/disorders/conditions closely allied to this one? Please give details We currently offer a service for TAR Syndrome at BGL. TAR Syndrome (Thrombocytopenia with Absent radius) is a rare genetic disorder that is characterized by the absence of the radius bone in the forearm, and a dramatically reduced platelet count (#274000). Dr Sarah Smithson has a special interest in skeletal and craniofacial disorders. Dr Ruth Newbury-Ecob, Clinical Genetics, UHB has a

4 16. Based on experience what will be the national (UK wide) activity, per annum, for: specialist interest in limb abnormalities, such as Holt- Oram Syndrome (#142900) which is characterised by heart and upper limb defects. It is difficult to assess the demand for the service as this has not been available to clinicians previously. We anticipate we may receive up to 10 referrals in the first year but this may increase with awareness of the service. 16a. Index cases ~10 in first year 16b. Family members where mutation is Not yet known, estimate of 30 (2 parents and one sib known for each case above) 17a. Does the laboratory have capacity to The capacity in BGL is available to meet demand for provide the expected national activity? UK. 17b. If your laboratory does not have capacity 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. 18. Please justify the requirement for another laboratory to provide this test e.g. insufficient national capacity.

5 EPIDEMIOLOGY 19a. Estimated prevalence of condition in the general UK population The prevalence of arthrogryposis is approx. 1/3000 [Hall et al 1982). The most common forms are DA1 and DA2B. Epidemiological data for the distal arthrogryposis (DA) syndromes are not available, but anecdotal data suggest that DA2B is the most common of the DAs and the most frequent cause of heritable arthrogryposis. The prevalence of DA appears to be similar across different populations although most of the individuals reported to date are of European ancestry. There is no known sex bias (Toydemir & Bamshad 2009) In a large study of over 350 patients with arthrogryposis, 44 (12.6%) patients with DA were identified. In another review, 35% of 155 patients with arthrogryposis were diagnosed with DA. In an epidemiological survey from western Sweden, 5 (7%) patients with DA syndromes were identified in a total of 68 patients with multiple congenital contractures. References: Bamshad, M., Van Heest, A. E., Pleasure, D. Arthrogryposis: a review and update. J. Bone Joint Surg. Am. 91: 40-46, 2009 Bamshad, M., Jorde, L. B., Carey, J. C. A revised and extended classification of the distal arthrogryposes. Am. J. Med. Genet. 65: , 1996 Sarwark JF, MacEwen GD, Scott CI, Jr. Amyoplasia (a common form of arthrogryposis). The Journal of bone and joint surgery Mar;72(3): Darin N, Kimber E, Kroksmark AK, Tulinius M. Multiple congenital contractures: birth prevalence, etiology, and outcome. J Pediatr Jan;140(1):61-7. Hall, J.G. (1985) Genetic aspects of arthrogryposis. Clin. Orthop. Relat. Res., 194, Hall, J G et al (1982) The distal arthrogryposes: Delineation of new entities review and nosologic discussion. Am J Med Genet: b. Estimated incidence of condition in the general UK population Please identify the information on which this is based 20. Estimated gene frequency (Carrier frequency or allele frequency) Please identify the information on which this is based Toydemir & Bamshad (2009) Sheldon-Hall Syndrome review. Orphanet Journal of Rare Diseases 4:11. Limited data for UK population available. Incidence of DA1 in US population is ~ 1:10,000. Bamshad M et al (1996) Am J Med Genet. 65: Hall JG (1985) Clin Orthop Relat Res. ;194: We have not been able to establish the carrier frequency from the literature. Please note that some cases have been described with de novo mutations. Tajsharghi et al (2007) Neurology 68:

6 21. Estimated penetrance Please identify the information on which this is based 22. Estimated prevalence of condition in the population of people that meet the Testing Criteria. Penetrance is highly variable in this condition so a mildly affected parent may have a severely affected child. Genetic testing will be very helpful in the diagnosis of mildly affected patients and family members. Target Population: 1. Patients with Distal Arthrogryposis type 2B 2. Patients with Distal Arthrogryposis type 1. INTENDED USE It is not known what proportion of DA2B cases have mutations in TPM2. Published mutations include the p.arg133trp mutation found in a mother and daughter with DA2B. Tajsharghi, H., Kimber, E., Holmgren, D., Tulinius, M., Oldfors, A. Distal arthrogryposis and muscle weakness associated with a beta-tropomyosin mutation. Neurology 68: , Currently only one mutation in TPM2 has been described in a patient with with DA1. Sung, S. S., Brassington, A.-M. E., Grannatt, K., Rutherford, A., Whitby, F. G., Krakowiak, P. A., Jorde, L. B., Carey, J. C., Bamshad, M. Mutations in genes encoding fast-twitch contractile proteins cause distal arthrogryposis syndromes. Am. J. Hum. Genet. 72: , Please tick either yes or no for each clinical purpose listed. Panel Tests: a panel test would not be used for pre symptomatic testing, carrier testing and pre natal testing as the familial mutation would already be known in this case and the full panel would not be required. Diagnosis Yes No Treatment Yes - possible influence on surgical management No Prognosis & management Yes No Presymptomatic testing ( for panel tests) Yes - to identify unaffected/minimally affected gene carrier No Carrier testing for family members ( for panel tests) Yes No Prenatal testing ( for panel tests) Yes - Possible No

7 TEST CHARACTERISTICS 24. 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. High Throughput Semi Automated Sequence analysis. Sensitivity %. To the best of our knowledge, no variant has been missed using a bi-directional sequencing approach. SCOBEC validation of unidirectional sequencing indicates a sensitivity of 99%. The sensitivity for detecting mutations in TPM2 will be 99% based on the mutations reported so far. Large deletions/duplications have not been reported in the TPM2 gene. Specificity > 99% 25. Clinical sensitivity and specificity of test in target population The clinical sensitivity of a test is the probability of a positive test result when condition is known to be present; the clinical specificity is the probability of a negative test result when disorder is known to be absent. The denominator in this case is the number with the disorder (for sensitivity) or the number without condition (for specificity). Clinical Sensitivity Currently only one mutation in TPM2 has been described in a patient with DA1. References: Sung, S. S., Brassington, A.-M. E., Grannatt, K., Rutherford, A., Whitby, F. G., Krakowiak, P. A., Jorde, L. B., Carey, J. C., Bamshad, M. Mutations in genes encoding fast-twitch contractile proteins cause distal arthrogryposis syndromes. Am. J. Hum. Genet. 72: , DA1 is also caused by mutations in the MYBPC1 gene (*160794) which we don t currently test (no UKGTN service). Collectively, mutations in the MYH3 (*160720), TNNI2 (*191043), and TNNT3 (*600692) genes account for about half of all studied cases of DA2B. It is not known what proportion of DA2B cases have mutations in TPM2. Published mutations include the p.arg133trp mutation found in a mother and daughter with DA2B. References: Toydemir, R. M., Rutherford, A., Whitby, F. G., Jorde, L. B., Carey, J. C., Bamshad, M. J. Mutations in embryonic myosin heavy chain (MYH3) cause Freeman-Sheldon syndrome and Sheldon- Hall syndrome. Nature Genet. 38: , Tajsharghi, H., Kimber, E., Holmgren, D., Tulinius, M., Oldfors, A. Distal arthrogryposis and muscle weakness associated with a beta-tropomyosin mutation. Neurology 68: , Clinical specificity : Presumed over 95%, depending on the basis of interpretation of sequence variants as consensus mutations, or as innocuous polymorphisms. For testing relatives: Clinical sensitivity and specificity: will both be 100% when the mutation is definitely pathogenic. 26. 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 condition or predisposition. It is measured by its positive predictive value (the probability of getting the condition given a positive test) and negative predictive value (the probability of not getting the condition given a negative test). Clinical validity: In an index case, finding one pathogenic mutation confirms the diagnosis in the majority of cases. We estimate that for index cases- Positive predictive value (PPV) = 100% for consensus mutations Negative predictive value (NPV) = greater uncertainty but likely to approach 100%

8 If looking at TPM2 alone the NPV is 100% but according to recent data by Beck et al (2013) Am J Med Genet A 161(3): , TPM2 mutations account for approx. 9% of cases of DA1 and DA2B overall. The paper reports that the genetic basis of DA1/DA2B can be explained in <50% of cases, although in this study the percentage of patients positive for a mutation out of the genes tested was 37%. Note: Cohort size: 153; genes tested TPM2, TNNT3, TNN12 and MYH3. However, for testing family members, PPV and NPV are both effectively 100% for carrier status using consensus mutations. 27. Testing pathway for tests where more than one gene is to be tested 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 will be added to the published Testing Criteria. Currently we are only developing a test for the TPM2 gene. CLINICAL UTILITY 28. How will the test change the management of the patient and/or alter clinical outcome? The DA group is clinically heterogeneous (with extensive phenotypic variability between and within families) and it can be very difficult to decipher the different types and importantly distinguish them from primary muscle and neurological disorders which can also present with congenital contractures. The prognosis in DA type 1 is usually good with appropriate physiotherapy and surgical intervention when necessary and furthermore patients have normal development. The prognosis in some of the neurological conditions may be very different so early diagnosis is important to advise parents correctly and initiate the right treatment. If the molecular genetic basis can be identified, it can be clearly established whether the parents carry the mutation and accurate genetic counselling provided. It is important to distinguish between the very low risk (if a de novo mutation) or high 50% risk (if present in a parent). In rare instances parents may request prenatal diagnosis if they have had a very severely affected infant before. Some patients may have breathing difficulties if there is analysis of the jaw and sometimes this requires a tracheostomy. 29. Benefits of the test for the patient & other family members Please provide a summary of the overall benefits of this test. Firstly testing will enable a precise diagnosis in this difficult group with clinical overlap with a wide variety of neurological conditions presenting with contractures. This will allow clinicians to decide on appropriate management and avoid invasive investigations such as muscle biopsy in some patients. Molecular investigation is important in order to further define and understand this disorder and provide accurate genetic counselling. In some families with a more severe phenotype the option for early prenatal diagnosis will be possible. 30. What will be the consequences for patients and family members if this test is not approved? Uncertain diagnosis, they may be misinformed about the outcome for their child, they may have another affected child without being aware of the risk. 31. 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 diagnosis is clinical supported by X ray investigations and the absence of any biochemical or muscle disorder. Very rare cases of congenital contractures (which mimic DA) may be caused by maternal myasthenia gravis where the mother produces antibodies to fetal acetylcholine receptors at the neuromuscular junction, then the antibodies may be measured in maternal serum. The great advantage of the molecular test is that numerous other invasive tests such as nerve conduction studies and muscle biopsy may be avoided if the diagnosis can be established early.

9 32. Please describe any specific ethical, legal or social issues with this particular test. There are no specific issues with this test. Parents would require counselling to understand the highly variable gene penetrance prior to testing. Prenatal diagnosis may only be requested in a few families for example if a child had been severely affected. 33. Only complete this question if there is previously approved Testing Criteria and you do not agree with it. Please provide revised Testing Criteria on the Testing Criteria form and explain here the changes and the reasons for the changes. 34. List the diagnostic tests/procedures that an index case no longer needs if this genetic test is available. Total cost tests/procedures no longer required Type of test Cost ( ) Costs and type of imaging procedures Brain MRI scan 230 Spine MRI scan Costs and types of laboratory pathology tests (other than molecular/cyto genetic test proposed in this Urine MPS gene dossier) Carnitines CPK Lactate Ammonia White cell enzymes Costs and types of physiological tests (e.g. ECG) Cost and types of other investigations/procedures (e.g. biopsy) Plasma amino acids and urine organic acids Nerve conduction studes EMG Muscle biopsy Based on the expected annual activity of index cases (Q15a), please calculate the estimated annual savings/investments based on information provided in Q33. Number of index cases expected annually (a) initially up to 10 Cost to provide tests for index cases if the (b) 1158 genetic test in this gene dossier was not available (see Q34) Total annual costs pre genetic test 10 x = Total annual costs to provide genetic test Total savings = x 522 = 5220 cost of genetic testing for index case

10 36. REAL LIFE CASE STUDY In collaboration with the clinical lead, describe TWO real case examples: 1. prior to availability of genetic test 2. post availability of genetic test to illustrate how the test improves patient experience and the costs involved. Case example one pre genetic test A young adult man with DA type 1 had been born with distal contractures of his hand and feet. These were treated with staged surgical procedures over the years and he was able to achieve good hand function; he had completely normal intellect. He had been incorrectly advised that he did not have a genetic condition and did not have access to genetic diagnosis or counselling prior to having his first child who was also affected with DA1, although more severely so. This came as a shock to him and he was initially very upset as he had not understood the risk to his children. The diagnosis of DA 1 was made on clinical and radiological grounds, but in this case access to genetic testing would have been helpful to delineate the type of arthrogryposis and confirm the genetic risk. Genetic testing would also be very helpful to those children who are the first to be affected in their families where the differential diagnosis in infancy can be quite broad. Case example two post genetic test The service is not yet available hence we are not able to provide this PRE GENETIC TEST COSTS Type of test Cost Costs and type of imaging procedures MRI scan 230 Costs and type of laboratory pathology tests Metabolic Costs and type of physiological tests (e.g. ECG) Nerve conduction 360 ( 180 each) and EMG Cost and type of other investigations/procedures (e.g. biopsy) Muscle Biopsy 538 Cost outpatient consultations (genetics and non genetics) Genetics and nongenetics 2000 Total cost pre genetic test Case example two post genetic test The service is not yet available hence we are not able to provide this as a case study POST GENETIC TEST COSTS Type of test Cost Costs and type of imaging procedures Not required - Costs and types laboratory pathology tests Not required - (other than molecular/cyto genetic proposed in this gene dossier) Cost of genetic test proposing in this gene dossier 522 Costs and type of physiological tests (e.g. ECG) Not required - Cost and type of other investigations/procedures (e.g. biopsy) Not required - Cost outpatient consultations (genetics and non genetics) As above 2000 Total cost post genetic test Estimated savings between two case examples described

11 Test name: Distal Arthrogryposis UKGTN Testing Criteria Approved name and symbol of disorder/condition(s): Arthrogryposis, Distal, Type 1A; DA1A Arthrogryposis, Distal, Type 2B; DA2B Approved name and symbol of gene(s): tropomyosin 2; TPM2 OMIM number(s): OMIM number(s): Patient name: Patient postcode: Name of referrer: Title/Position: Referrals will only be accepted from one of the following: Referrer Consultant Clinical Geneticist Date of birth: NHS number: Lab ID: Tick if this refers to you. Minimum criteria required for testing to be appropriate as stated in the Gene Dossier: Criteria Distal arthrogryposes characterised by congenital contractures of hand and foot and limited involvement of proximal joints AND Absence of primary neurological and/or muscle disease AND Affected with two or more of the following: Upper limb: camptodactyly or pseudocamptodactyly hypoplastic and/or absent flexion creases, overriding fingers, and ulnar deviation at the wrist. Lower limb: talipes equinovarus, calcaneovalgus deformities, vertical talus, and/or metatarsus varus (Distinct facial features: triangular face, prominent nasolabial folds, downslanting palpebral fissures, small mouth). OR At least one major diagnostic criterion where first-degree family member (i.e., a parent or a sibling) meets the above diagnostic criteria At risk family members where familial mutation is known. 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. -