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 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 Gene name(s) Sandhoff Disease GM2-GANGLIOSIDOSIS, TYPE II HEXOSAMINIDASES A AND B DEFICIENCY Sandhoff disease is a progressive neurodegenerative disorder characterized by an accumulation of GM2 gangliosides, particularly in neurons, and is clinically indistinguishable from Tay-Sachs disease. Muscular weakness begins in first six months of life. Degeneration of mental capabilities, coordination, motor skills and tone is progressive and continual. Motor milestones (e.g. crawling, ability to sit up) are severely retarded and eventually begin to regress. Startle reaction, early blindness and retinal cherry red spots become apparent. Typical facies and macrocephaly have been reported. Hepatosplenomegaly has been reported. Death is frequently caused by respiratory problems, including pneumonia, bronchopneumonia and associated secondary infections. Life span is typically less than three years for the infantile type. Two less common subtypes of the disease exist, a juvenile onset (onset by 3-5 years, mortality frequently in teenage years) and adult onset disease (motor functions only clinically affected beyond teenage years, lifespan likely reduced but not as severely in other forms). The adult and infantile types are associated in particular with certain specific missense changes in the HEXB gene, which have been generally hypothesised to represent less severe dysfunctions in the hexosaminidase protein, however, significant heterogeneity has been reported in the phenotype conferred by some of these mutations (e.g. Pro405Leu has been reported as causing adultonset forms in compound heterozygosity with a large deletion, but has also been reported in one homozygous case to cause an earlier, juvenile onset form of disease). Autosomal recessive (particularly autozygous) HEXB OMIM number for gene(s) Gene alternative names Hexosaminidase B Please provide any alternative names you wish listed Gene description(s) (including 5q13 number of amplicons). Protein product is an isoenzyme of hexosaminidase, alongside protein product of HEXA (OMIM *606869), mutations in which cause Tay-Sachs. 1

2 Mutational spectrum for which you 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? 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 14 exons, analysed in 14 amplicons (sequencing) Encodes 556 amino acid protein 1671 coding nucleotides Testing comprises bi-directional dideoxy sequencing of the entire coding region plus intron/exon boundaries. A missense mutation in ex11 (c.1376c>a (p.asp459ala)) has been detected in all but two of the affected probands (n=9) tested in our lab from Pakistani origin, including individuals referred from Birmingham and London; indicating a founder mutation in this population. A 27-kb deletion including exons 1-5 has been reported in multiple patients; this testing strategy does not detect this but homozygotes would be indicated by non-amplification of these exons. Dideoxy (Sanger) sequencing of exon 1-14, following PCR amplification. In individuals with one confirmed mutation, are apparently homozygous for a mutation in exons 1-5 or where exons 1-5 are not apparently amplifiable, will use allele-specific PCR test as described by Neote et al. (see above) to assay for possible common deletion allele. Sequence protocols optimised and validated in-house according to local procedure. Primers sequences checked for location, BLAST hits and SNPs (on an annual basis) using online resources (ensembl and NGRL SNPcheck). PCR conditions optimised using PCRs and annealing temperature gradients. Sequence information obtained and used for diagnostic scoring/reporting is checked against the reference sequences available at Ensembl and NCBI. Yes If Yes: Number of reports issued: 24 Number of reports mutation positive: 21 Number of reports mutation negative: 3 Since mid-2006 (approx 4 years) Yes Please provide details Due to the prevalence of consanguineous marriages in the local Asian (Pakistani) community, which makes up a large percentage of the Bradford region, there is a high prevalence of autozygous disease seen by Clinical Genetics and local Paediatric depts, with several clinicians with specialisations and experience in this area. The laboratory offers services for a number of rare recessive disorders seen in the local Pakistani population, for example Meckel Gruber Syndrome and Aicardi Goutiere Syndrome. The laboratory works closely with research groups within the Leeds Institute of Molecular Medicine (Leeds University) to translate research findings into diagnostics testing services where a clinical need is demonstrated. 2

3 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 if this gene dossier is approved and recommended for NHS funding? Based on experience how many tests will be required nationally (UK wide)? National Activity (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. (See Index cases: Approximately 1-5 Family members where mutation is known: Approximately 1-10 Index cases: 20 (total number of UK births with Sandhoff is likely to be fewer than this, see frequency data below) Family members where mutation is known: 50 Index cases: 10 (approximate estimate) Family members where mutation is known: Assuming 700,000 live births and prevalence of 1 in 360,000 (given carrier frequency estimates, see below), approx 2 per year; however, local data shows high prevalence in Pakistani community (with autozygous inheritance), with three quarters of local referrals from this population. Autozygosity in this (and possibly other) populations revises estimate upwards. Will be able to service the entire UK demand. 3

4 Epidemiology Estimated prevalence of disease in the general UK population Estimated gene frequency (Carrier frequency or allele frequency) Estimated penetrance 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 No published data in UK population. Possibly under-reported due to similarity to Tay-Sachs, complex clinical diagnosis, and less severe adult-onset forms. Carrier frequency (see below) suggests possible 1 in 360,000 births with random mating. However, literature (Drousiotou et al, Hum Genet Jul; 107(1):12-7) suggests potentially large variations in carrier frequency in different ethnic populations; prevalence of disease likely to be especially high in autozygous populations. Carrier frequency estimated at 1/600 in non-jewish population in North America. No significant data from UK (Cantor & Kaback, Am J Hum Genet, 37: A48, 1985); carrier frequency assumed to vary greatly in different ethnic founder populations. A smaller study found a carrier frequency of 1/161 in American individuals of Scottish, English or Welsh descent, and a slightly higher rate in Italian Americans (4 in 436 individuals; Branda, Tomczak & Natowicz, Genet Test, 8: , 2004). 100% (no evidence in literature of unaffected individuals with biallelic mutations; milder adult onset forms have been reported with missense mutations) Any individual with apparent Sandhoff; ideally should be confirmed by biochemical/enzymatic analysis. Current general practice for biochemical testing of Sandhoff/Tay-Sachs (GM2 gangliosidosis) is to measure total hexosaminidase and hexosaminidase A activities in plasma or cultured leukocytes/fibroblasts. This can also be accomplished from newborn screening card blood spots (Chamoles et al, Clin Chim Acta, 318: , 2002). Any relative of genetically or biochemically confirmed Sandhoff patients. No published data; likely rare in general population but 100% (or close to) for individuals with biochemical confirmation. All but one local family with confirmed mutations are Pakistani in origin. Highest apparent reported incidence in an inbreeding population possibly Cypriot Christian Maronites (3 different families in a population of less than 7000), with a carrier freq ~14% in random Maronite samples (Drousiotou et al, Hum Genet Jul;107(1):12-7). 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 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. 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 Laboratory quotes >95% analytical sensitivity of dideoxy sequencing data. Statistical analysis demonstrates >99% sensitivity (internal data). Specificity 100% as far as we know no known false negatives reported using this technique in this laboratory s experience. From limited local data, clinical sensitivity is 100%. In reality, clinical sensitivity is unlikely to be 100% as testing strategy (at present) will not necessarily detect large deletions (which have been shown to be potential causes of disease) or epigenetic factors. However, as far as we are aware, there are no cases of biochemically/clinically confirmed Sandhoff in the literature without a detectable genetic cause, so clinical sensitivity of 100% may be theoretically applicable. Clinical specificity is so far 100%; no unaffected or carrier individuals have been found to have biallelic mutations. No such cases have been presented in the literature. Positive and negative genetic tests for Sandhoff disease should confer 100% clinical validity (i.e. the PPV and NPV of the test, in regard to biochemically-confirmed/excluded SD patients, appears to be 100% in the literature and in our experience). PPV is theoretically and actually 100% in our experience, although NPV (whilst currently 100%) is probably <100% due to the possible presence of large genomic rearrangements, some of which would be undetected in heterozygous patients and (in some cases such as putative inversions, duplications etc.) may potentially not be detected in homozygous patients. Urgent referrals for individuals of Pakistani origin will be tested for founder mutation in exon 11 first, accounting for over half the mutations in this population. There is no effective treatment for individuals with genetically or biochemically confirmed SD. The National Institute of Neurological Diseases and Stroke (US) states: There is no specific treatment for Sandhoff disease. Supportive treatment includes proper nutrition and hydration and keeping the airway open. Anticonvulsants may initially control seizures. Genetic diagnosis would not necessarily facilitate this care pathway, as treatment (such as it exists) is generally palliative. The genetic diagnosis is likely to feed into the clinical care pathway in terms of family planning decisions and prenatal diagnosis 5

6 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? The sensitivity and specificity of the biochemical test for hexosaminidase activity is not 100%, particularly for carrier testing (one study states only a 95% sensitivity for carrier tests, Cantor & Kaback, Am J Hum Genet, 41(1): 16-26, 1987). Genetic testing represents a likely gold standard for identifying mutations in families with an affected proband, and thereby facilitating future prenatal diagnoses and estimating carrier risks more accurately. This test would replace the need for biochemical testing to ascertain the carrier status in families where Sandhoff disease has been diagnosed. The consequences of not doing this test would be a reliance on the biochemical test for carrier testing and inaccurate risk to pregnancies given to families. The impact would be mainly felt by the UK Pakistani population where this disease is more frequent (the majority based in Bradford, Birmingham and London). To provide a definitive diagnosis for families. Once a diagnosis has been established, to provide accurate carrier testing and prenatal testing. Biochemical test involves measurement of hexosaminidase activity levels on substrate. Main problem is a <100% sensitivity level, especially in carrier tests where sensitivity may be as low as 95% (Cantor & Kaback, Am J Hum Genet, 41(1): 16-26, 1987). Genetic analysis of known familial mutations (using a positive control) should allow a sensitivity and specificity of 100% for carrier tests. N/A 6

7 UKGTN Testing Criteria Name of Disease(s): SANDHOFF DISEASE (268800) Name of gene(s): hexosaminidase B (beta polypeptide); HEXB ( ) 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 paediatric neurologists Consultant paediatricians Tick if this refers to you. Minimum criteria required for testing to be appropriate as stated in the Gene Dossier: Criteria Biochemically-confirmed (total hexosaminidase and hexosaminidase A) OR ethnic likelihood of founder mutation for Sandhoff disease At risk family members with known mutation 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. 7