Proposal form for the evaluation of a genetic test for NHS Service Gene Dossier/Additional Provider TEST DISEASE/CONDITION POPULATION TRIAD Submitting laboratory: Manchester RGC Approved: September 2013 1. Disease/condition approved name and symbol as published on the OMIM database (alternative names will be listed on the UKGTN website) OHDO SYNDROME, SBBYS VARIANT; SBBYSS OHDO SYNDROME GENITOPATELLAR SYNDROME; GTPTS 2. OMIM number for disease/condition 3. Disease/condition please provide a brief description of the characteristics of the disease/condition and prognosis for affected individuals. Please provide this information in laymen s terms. 603736 249620 606170 Blepharophimosis, an abnormal narrowing of the palpebral fissures, is seen in association with intellectual disability in disorders collectively known as the blepharophimosis -mental retardation syndromes 1. Though the first of these was described by Ohdo et al. 2, the most distinctive phenotype is the Say- Barber-Biesecker-Young-Simpson syndrome (SBBYSS) 3 which is characterized by a distinctive facial appearance with severe blepharophimosis, an immobile mask-like face, a bulbous nasal tip, and small mouth with thin upper lip. Skeletal problems include joint laxity, abnormally long thumbs and great toes and dislocated or hypoplastic patellae. The symptoms and signs overlap with Genitopatellar syndrome which has also been found to be caused by mutations in KAT6B. 3 1. Ohdo et al J.Med.Genet 23, 242-244 (1986). 2. Clayton-Smith et al A.J.Hum. Genet. 89, 675-681. (2011). 3. Campeau et al A.J.Hum. Genet. 90, 1-8, (2012). 4. Disease/condition mode of Autosomal dominant most cases are de-novo mutations inheritance 5. Gene approved name(s) and K(lysine) acetyltransferase 6B; KAT6B symbol as published on HUGO database (alternative names will be listed on the UKGTN website) 6. OMIM number for gene(s) 605880 7. Gene description(s) 26 amplicons; the majority of mutations found within exon 18 7b. Number of amplicons to 26 amplicons provide this test 7c. MolU/Cyto band that this test GenU Band F is assigned to 8. Mutational spectrum for which There are no known common mutations. The test by Sanger you test including details of sequencing will detect all the point and small indel mutations known common mutations described to date. 9. Technical method(s) Sanger sequencing 10. Validation process Please explain how this test has been validated for use in your laboratory The entire coding region of the KAT6B gene was sequenced in a total of 23 clinically ascertained patients. In this cohort 16 patients were found to have protein truncating mutations (69%). The test has been re-designed to diagnostic standards and comprises 26 amplicons. This test has undergone validation trials for reproducibility, repeatability and ruggedness on samples from patients of known genotype.
11a. Are you providing this test already? No X Yes 11b. If yes, how many reports 58 have you produced? 11c. Number of reports mutation positive 28 11d. Number of reports mutation 30 negative 12. For how long have you been since April 2012 providing this service? 13a. Is there specialised local clinical/research expertise for this disease? No X Yes 13b. If yes, please provide details Prof Jill Clayton-Smith published the research series describing de novo KAT6B mutations in patients with the SBBYS (Ohdo) phenotype and confirmed the condition as a distinct clinical entity. 14. Are you testing for other genes/diseases/conditions closely allied to this one? Please give details Tests for neuro-developmental / dysmorphic syndromes within our portfolio include Angelman syndrome (UBE3A), Pitt Hopkins, Kabuki syndrome. Your current activity If applicable - How 77 many tests do you currently provide annually in your laboratory? 15a. Index cases 36 15b. Family members where 13 mutation is known Your capacity if Gene Dossier 150 cases per annum 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? 16a. Index cases 50-75 16b. Family members where mutation is known Based on experience how many tests will be required nationally (UK wide) per annum? Please identify the information on which this is based 25-50 130 (based on numbers required for Ohdo syndrome. Guys and St Thomas provide activity numbers based on the rarer GTPTS) 17a. Index cases 100 17b. Family members where 30 mutation is known 18. National activity (England, 50 100 cases per annum Scotland, Wales & Northern Ireland). If your laboratory is unable to We are not aware of other centres providing this test. 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 19. Estimated prevalence 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 21. Estimated penetrance Please identify the information on which this is based 22. Estimated prevalence of condition in the target population. The target population is the group of people that meet the minimum criteria as listed in the Testing Criteria. INTENDED USE Based on figures from the North West region a study by Day and Clayton-Smith estimated the prevalence of the condition at 1 in 100,000 Not known most cases are de novo mutations The penetrance is high in the limited numbers of families studied. The target group is Individuals with the minimum set of features compatible with Ohdo/genito-patellar syndromes described in the testing criteria. The detection rate in the validation series was high (69%) suggesting that careful ascertainment by clinical geneticists will result in a high diagnostic yield. In a service series we would expect the detection rate to drop to perhaps 30%. 23. Please tick the relevant clinical purpose of testing Diagnosis X Yes No Treatment X Yes No Prognosis & management X Yes No Presymptomatic testing Yes X No Carrier testing for family members X Yes No Prenatal testing X Yes No
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. On the basis of re-sequencing of positive controls we estimate that the analytical sensitivity and specificity of the technique used (Sanger sequencing) will be greater than 98%. 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 disease is known to be absent. The denominator in this case is the number with the disease (for sensitivity) or the number without condition (for specificity). Clinical sensitivity Up until now, only one gene, KAT6B has been identified to cause Ohdo syndrome. In our published series 69% of patients had mutations identified by sequencing. The research series did not include assays for whole exon duplications and deletions. It is possible that the patients in whom no mutation was detected do not have Ohdo Syndrome and that that there are other genes, perhaps acting in the same pathway which cause the condition. We are collaborating in further research to determine whether there are other causative genes. Clinical specificity The clinical specificity is high. No point or small indel mutations have been detected in control samples and in unaffected parents. Campeau et al did not detect truncating mutations in KAT6B in 2,000 control individuals. Penetrance The penetrance of mutations in KAT6B appears to be high. All patients with mutations have exhibited a phenotype although the severity of the phenotype may vary within a family. No unaffected parents have had mutations. 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). This is a rare condition and information is scarce. To date, all patients identified to have KAT6B mutations have had some features of Ohdo Syndrome. 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. N/A The current analysis is a gene scan restricted to the KAT6B gene. CLINICAL UTILITY 28. How will the test add to the management of the patient or alter clinical outcome? Learning disability is common affecting 3% of the general population. The cause remains unknown in 50%. Identifying a cause for learning disability, including that associated with Ohdo Syndrome has several benefits. Utility of a positive test result: It allows confirmation of the clinical diagnosis and provides an explanation for the parents. It informs management of the child e.g. help with feeding difficulties and initiates screening for cardiac, thyroid, hearing, ocular and dental abnormalities. It can alert the doctors managing the child to the possibility of rare complications.
It facilitates accurate genetic counselling confirming the low recurrence risk for Ohdo syndrome in which many cases are due to de novo mutations. This can be reassuring for parents although gonadal mosaicism has been described; the option of prenatal diagnosis is therefore relevant. This can be useful when parents are making future reproductive decisions. It helps parents to access support for education and social care through informal carers networks If the diagnosis is made it means that doctors can stop searching for other causes of learning disability and the patients are saved from having to undergo more investigations, many of which might be invasive. Utility of a negative test result: will allow prioritisation of mutation negative cases for additional aetiological investigations including CGH array, other single gene analyses and research / exome studies aimed at identifying other genes causing Ohdo syndrome. 29. How will the availability of this test impact on patient and family life? Detection of a mutation establishes a diagnosis and ends further investigation. It leads to better management of the condition and promises better adjustment of the family to meet the needs of the child with Ohdo syndrome. The diagnosis opens reproductive options for parents. 30. Benefits of the test Please provide a summary of the overall benefits of this test. See Q28 above: the test where a mutation is detected facilitates screening to prevent complications and removes the need for further tests enabling accurate counselling. 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. Clinical diagnosis is difficult and imprecise due to the clinical overlap between Ohdo/genito-patellar syndromes and a large number of other conditions. There are no alternative tests to establish a diagnosis 32. Please describe any specific ethical, legal or social issues with this particular test. There are no ethical issues with this test beyond those raised by genetic testing more generally. 33. The Testing Criteria must be completed where Testing Criteria are not already available. If Testing Criteria are available, do you agree with them Yes/No If No, please propose alternative Testing Criteria AND please explain here the reasons for the changes. 34. Savings or investment per annum in the diagnostic pathway based on national expected activity, cost of diagnostics avoided and cost of genetic test. Please show calculations. The cost of testing 100 index cases is estimated at 48,000. Above (Q22) we estimate that amongst this group the mutation detection rate in a service setting is 30% resulting in a saving (Q35 below) of 30x 2,200 = 66,000 in alternative investigative procedures. So in total this service offers a net saving of approximately 66,000 48,000 = 18,000 per annum. 35. List the diagnostic tests/procedures that would no longer be required with costs. A child born with Ohdo syndrome might typically have investigations in the first year of life for hypotonia which will vary in number and sequence but may include; metabolic tests, muscle biopsy, thyroid function test, serum CPK and MRI scan (total > 2,000). Genetic investigations may include Prader Willi syndrome, SMA and VLCFA (total ~ 1,000). In infancy tests may include the CFC pathway, myotonic dystrophy, BPES and MIDI (total ~ 1,400). If, on average, half these investigations are avoided by the targeted genetic test then there is an estimated saving of 2,200 for each case of Ohdo syndrome confirmed by an early request of a test for KAT6B mutations.
36. REAL LIFE CASE STUDY In collaboration with the clinical lead, describe a real case example to illustrate how the test would improve patient experience. A baby was noted to be hypotonic after birth. A congenital heart defect, cleft palate and unusual facial features were noted. A number of investigations were carried out including routine karyotype, FISH 22q11, microarray analysis and 15q11 methylation to rule out Prader-Willi syndrome and FOXL1 analysis to rule out BPES syndrome. All gave negative results. The baby fed poorly and required a gastrostomy and surgery to repair the palate. She had severe developmental delay. A clinical diagnosis of Ohdo syndrome, Say Barber, Biesecker type was assigned. Further tests followed as they became available including subtelomeric FISH and 1Mb array studies. This was the parents first child. She required a great deal of medical care and because the cause of this condition was unknown they were too worried to contemplate further pregnancies, especially as there had been a family reported in the literature who had had two affected children with this condition. At ten years old the child was confirmed to have a de novo mutation within KAT6B. The parents can finally understand the cause of their child s condition and have been given a gonadal mosaic risk for further pregnancies, with the possibility of a prenatal test if they wished. They have been able to meet with other parents who have children with the same condition and have benefited greatly from this. 37. For the case example, if there are cost savings, please provide these below: In the case described in Q36 microarray analysis using a standard NHS array is likely to remain the first investigation chosen and is unlikely to be replaced by KAT6B mutation analysis. Standard metabolic tests including CPK analysis are also likely to be undertaken. Tests for PWS, FOXL1, SMA and myotonic dystrophy analysis would cost approximately 700. The net saving of early use of KAT6B testing (not considering the cost of array analysis which is likely to remain a fixed cost in this pathway) would have been approximately 200 in this case. In many typical cases savings would be greater as other genes would also be tested or investigations such as muscle biopsy would be considered in view of the hypotonia. 38. Estimated savings for case example described 200.00
Test name: Genitopatellar and Ohdo Syndrome UKGTN Testing Criteria Approved name and symbol of disease/condition(s): Ohdo Syndrome, SBBYS Variant; SBBYSS Ohdo Syndrome Approved name and symbol of gene(s): K(lysine) acetyltransferase 6B; KAT6B OMIM number(s): 603736 249620 OMIM number(s): 605880 Patient name: Patient postcode: Date of birth: NHS number: Name of referrer: Title/Position: Referrals will only be accepted from one of the following: Referrer Consultant Clinical Geneticists Lab ID: Tick if this refers to you. Minimum criteria required for testing to be appropriate as stated in the Gene Dossier: Criteria Two major features OR one major feature and two minor features are required: Major features: Immobile mask-like face Blepharophimosis/ptosis Thyroid anomalies Patellar hypoplasia/agenesis Minor features: Lacrimal duct anomalies Long thumbs/great toes Congenital heart defect Dental anomalies (hypoplastic teeth and /or delayed eruption of teeth) Cleft palate Genital anomalies (males: cryptorchidism) Hypotonia Global developmental delay / intellectual disability OR 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
Test name: Genitopatellar and Ohdo Syndrome UKGTN Testing Criteria Approved name and symbol of disease/condition(s): Genitopatellar Syndrome; GTPTS Approved name and symbol of gene(s): K(lysine) acetyltransferase 6B; KAT6B OMIM number(s): 606170 OMIM number(s): 605880 Patient name: Patient postcode: Name of referrer: Title/Position: Date of birth: NHS number: Lab ID: Referrals will only be accepted from one of the following: Referrer Consultant Clinical Geneticists 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 Two major features OR one major feature and two minor features are required: Major features: Genital anomalies (females: clitoromegaly and/or hypoplasia of the labia minora or majora; males: cryptorchidism and scrotal hypoplasia) Patellar hypoplasia/agenesis Flexion contractures at the hips and knees (including club feet) Agenesis of the corpus callosum with microcephaly Hydronephrosis and/or multiple renal cysts Minor features: Congenital heart defect Dental anomalies (delayed eruption of teeth) Thyroid anomalies Anal anomalies Hypotonia Global developmental delay/intellectual disability OR At risk family members where familial mutation is known. 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.