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) 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) Validation Process Note: please eplain 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? Progressive familial intrahepatic cholestasis PFIC3; MDR3 deficiency; cholestasis, progressive familial intrahepatic, with elevated serum gammaglutamyltransferase Progressive familial intrahepatic cholestasis type 3 is an autosomal recessive liver disorder characterized by early onset of cholestasis that progresses to hepatic fibrosis, cirrhosis, and end-stage liver disease in childhood. Autosomal recessive ABCB ATP-binding cassette, subfamily B, member 11; P- glycoprotein 3; PGY3; multidrug resistance 3; MDR3 ABCB4-26 amplicons Nonsense, missense, frameshift, small indels, splice site mutations Direct sequencing Direct sequencing in high throughput format used in laboratory for many conditions. Analysis of sequencing by mutation surveyor validated on a panel of 30 patients compared to manual methods. Primers all SNP checked using Manchester website. New amplicons tested using at least 8 normal controls to check quality and identity of sequences produced. Yes If Yes: Number of reports issued: 21 Number of reports mutation positive: 5(all of these were variants of unknown clinical significance) Number of reports mutation negative: 16 Since Jan

2 Is there specialised local clinical/research epertise for this disease? Yes Please provide details 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 if this gene dossier is approved and recommended for NHS funding? Based on eperience 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 eample, 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. Dr Jane Hartley Consultant hepatologist, Birmingham Children s Hospital Childhood liver diseases PFIC type 1, PFIC type 2, Niemann Pick type C, ARC, NICCD (Citrin deficiency) Inde cases: 21 Family members where mutation is known: 2 (Based on 2010 only) Inde cases: Family members where mutation is known: 100 Annual audit of liver activity (with review of 3 previous years) estimates the number of children who may require genetic testing for PFIC is approimately 32 per year This is based on the eperience and figures from the Liver Unit at Birmingham Children s Hospital which is one of the main centres for treatment of liver disease in children. Testing is also carried out at Kings laboratory is not listed on UKGTN. Laboratory is a research lab but they do issue reports. It is not clear how many samples they can accept. 2

3 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 The true incidence of PFIC (including type 3) is not precisely known, but PFIC is considered a rare disease with an estimated incidence of 1/50,000 to 1/100,000 births. All types of PFIC eist worldwide. Both sees seem to be equally affected. Davit-Spraul et al Progressive familial intrahepatic cholestasis Orphanet Journal of Rare Diseases 2009, 4:1 Carrier frequency is unknown (Gene Clinics) Unknown but presumed high Infants with intrahepatic cholestasis, pruritis or diarrhoea. Older children or adults with episodes of uneplained cholestasis because ABCB4 is also associated with a milder disease called Benign Recurrent Intrahepatic Cholestasis type 3 (BRIC3). PFIC (all types) estimated to be 10-15% Davit-Spraul et al Progressive familial intrahepatic cholestasis Orphanet Journal of Rare Diseases 2009, 4:1 Intended Use (Please use the questions in Anne A to inform your answers) Please tick the relevant clinical purpose of testing Diagnosis Treatment Prognosis & Management Presymptomatic testing Risk Assessment for family members Risk Assessment prenatal testing YES NO 3

4 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 epected 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 Appendi A) Please provide a description of the clinical care pathway. Sensitivity of sequencing is >99%. This test will not detect deletions or duplications in the ABCB4 gene; the fraction of PFIC3 patients this affects is unknown at present. Sensitivity 26% Specificity >99% ABCB4 sequencing in infants would only be carried out in those with cholestasis and high GGT. This clinical phenotype is indistinguishable from many other causes of neonatal cholestasis. Liver biopsy is also non-specific with portal inflammation and ductular proliferation. The only method of identifying PFIC3 accurately is through mutation identification and therefore in this population the positive and negative predictive value is 100%. In other populations such as those with intrahepatic cholestasis in pregnancy this is not so specific in that the clinical phenotype can arise without mutations in ABCB4. The positive and negative predictive value therefore in the adult population cannot be quantified. Neonatal cholestasis with high GGT and normal colour stool Normal ultrasound scan to eclude obstructive cause Alpha 1 antitrypsin deficiency, metabolic, infective, and endocrine causes ecluded by blood and urine sampling Liver biopsy: non-specific inflammation with ductular proliferation Refer for ABCB4 sequencing Cholestasis in infancy is the presenting feature of many liver disorders therefore making a diagnosis can be difficult. Often there is a prolonged period between presentation and making the diagnosis leading to multiple hospital admissions and invasive procedures such as liver biopsies. Confirming the diagnosis by identifying mutations in ABCB4 facilitates clinical management and enables accurate counselling of families as to the likely 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 eplain 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? long-term prognosis. Children with PFIC3 require intensive support with high calorie medium chain triglyceride feeds often by nasogastric feeding and fat-soluble vitamin supplementation. The infants are often etremely pruritic leading to a poor quality of life for all the family and requiring multiple medications, which are often poorly effective. Most children with PFIC3 will require liver transplant in childhood as a life saving procedure. The etrahepatic manifestations (diarrhoea and pancreatitis) may only become manifest following transplantation. By providing a diagnosis intensive management to support the liver can be instigated prior to the development of complications. Invasive investigations will not be required and repeat investigations, which may be carried out when there is diagnostic uncertainty (such as liver biopsy, which is associated with morbidity and mortality), can be avoided. The clinical management of the child is optimised at an earlier stage and the essential counselling of the families for timely biliary diversion surgery or liver transplantation is facilitated. The test will reduce the number of admissions to hospital. It will reduce the number of children who develop complications which have developed due to not maimising the supportive management. It will facilitate timing of transplantation i.e. the diagnosis of PFIC1 means the child is likely to need transplantation and therefore the timing can be planned. Without a diagnosis there may be a delay. Diagnostic uncertainty leading to reduced input of intensive nutritional support, repeated hospitalisation for invasive procedures such as liver biopsy, inability to be able to prognosticate and therefore provide advice as to timing of biliary diversion or transplantation. The identification of mutations facilitates optimal medical management to support the liver and listing for liver transplant at the best possible time. There are no alternative methods of accurate diagnosing PFIC3 5

6 UKGTN Testing Criteria Name of Disease(s): CHOLESTASIS, PROGRESSIVE FAMILIAL INTRAHEPATIC, 3; PFIC3 (602347) Name of gene(s): ATP-binding cassette, sub-family B (MDR/TAP), member 4; ABCB4 (171060) 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 Liver Specialist Consultant Hepatology Paediatrician Consultant Clinical Geneticist Tick if this refers to you. Minimum criteria required for testing to be appropriate as stated in the Gene Dossier: Criteria Cholestasis associated with raised gamma glutamyl transferase (GGT) 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. 6

7 Neonatal cholestasis Low GGT High GGT Diarrhoea Pancreatitis Sensorineural deafness ATP8B1 ABCB11 If no mutations identified Contractures Renal dysfunction VPS33B If no mutations identified Low birth weight Poor weight gain Hepatomegaly Haemolytic anaemia Hypoglycaemia Hypoproteinaemia SLC25A13 Hepatosplenomegaly Neonatal hepatitis (can be severe) Older child: Supranuclear vertical gaze palsy Gelastic catapley Neurodegeneration VIPAR NPC1 ABCB4 If no mutations identified NPC2 7