1. health and fitness
2. disease

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
OHDO SYNDROME, SBBYS VARIANT; SBBYSS
name and symbol as published
OHDO SYNDROME
on the OMIM database (alternative
GENITOPATELLAR SYNDROME; GTPTS
names will be listed on the UKGTN website)
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.
4. Disease/condition – mode of
inheritance
5. Gene – approved name(s) and
symbol as published on HUGO
database (alternative names will be listed
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 syndromes1. Though the first of these was described
by Ohdo et al.2, the most distinctive phenotype is the SayBarber-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).
Autosomal dominant – most cases are de-novo mutations
K(lysine) acetyltransferase 6B; KAT6B
on the UKGTN website)
6. OMIM number for gene(s)
7. Gene – description(s)
7b. Number of amplicons to
provide this test
7c. MolU/Cyto band that this test
is assigned to
8. Mutational spectrum for which
you test including details of
known common mutations
9. Technical method(s)
10. Validation process
Please explain how this test has
been validated for use in your
laboratory
Approval Date: Sept 2013
605880
26 amplicons; the majority of mutations found within exon 18
26 amplicons
GenU Band F
There are no known common mutations. The test by Sanger
sequencing will detect all the point and small indel mutations
described to date.
Sanger sequencing
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.
Submitting Laboratory: Manchester RGC
Copyright UKGTN © 2013
11a. Are you providing this test
already?
11b. If yes, how many reports
have you produced?
11c. Number of reports mutation
positive
11d. Number of reports mutation
negative
12. For how long have you been
providing this service?
13a. Is there specialised local
clinical/research expertise for
this disease?
13b. If yes, please provide details
14. Are you testing for other
genes/diseases/conditions
closely allied to this one? Please
No
X
Yes
58
28
30
since April 2012
No
X
Yes
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.
Tests for neuro-developmental / dysmorphic syndromes within
our portfolio include Angelman syndrome (UBE3A), Pitt Hopkins,
Kabuki syndrome.
give details
Your current activity If applicable - How
77
many tests do you currently provide annually in
your laboratory?
15a. Index cases
15b. Family members where
mutation is known
Your capacity if Gene Dossier
approved How many tests will you be able to
36
13
150 cases per annum
provide annually in your laboratory if this gene
dossier is approved and recommended for NHS
funding?
16a. Index cases
16b. Family members where
mutation is known
Based on experience how many
tests will be required nationally
(UK wide) per annum? Please identify
50-75
25- 50
130 (based on numbers required for Ohdo syndrome. Guys and
St Thomas’ provide activity numbers based on the rarer GTPTS)
the information on which this is based
17a. Index cases
17b. Family members where
mutation is known
18. National activity (England,
Scotland, Wales & Northern
Ireland). If your laboratory is unable to
100
30
50 – 100 cases per annum
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”.
Approval Date: Sept 2013
Submitting Laboratory: Manchester RGC
Copyright UKGTN © 2013
EPIDEMIOLOGY
19. Estimated prevalence of
condition in the general UK
population
Please identify the information on
which this is based
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
20. Estimated gene frequency
(Carrier frequency or allele
frequency)
Please identify the information on
which this is based
Not known – most cases are de novo mutations
21. Estimated penetrance
Please identify the information on
which this is based
The penetrance is high in the limited numbers of families studied.
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.
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%.
INTENDED USE
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
Approval Date: Sept 2013
Submitting Laboratory: Manchester RGC
Copyright UKGTN © 2013
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.
Approval Date: Sept 2013
Submitting Laboratory: Manchester RGC
Copyright UKGTN © 2013
•
•
•
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.
Approval Date: Sept 2013
Submitting Laboratory: Manchester RGC
Copyright UKGTN © 2013
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
Approval Date: Sept 2013
Submitting Laboratory: Manchester RGC
Copyright UKGTN © 2013
UKGTN Testing Criteria
Test name:
Genitopatellar and Ohdo Syndrome
Approved name and symbol of disease/condition(s):
Ohdo Syndrome, SBBYS Variant; SBBYSS
Ohdo Syndrome
OMIM number(s):
603736
249620
Approved name and symbol of gene(s):
K(lysine) acetyltransferase 6B; KAT6B
OMIM number(s):
605880
Patient name:
Date of birth:
Patient postcode:
NHS number:
Name of referrer:
Title/Position:
Lab ID:
Referrals will only be accepted from one of the following:
Referrer
Tick if this refers to
you.
Consultant Clinical Geneticists
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:
• 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.
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
Approval Date: Sept 2013
Submitting Laboratory: Manchester RGC
Copyright UKGTN © 2013
UKGTN Testing Criteria
Test name:
Genitopatellar and Ohdo Syndrome
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:
Date of birth:
Patient postcode:
NHS number:
Name of referrer:
Title/Position:
Lab ID:
Referrals will only be accepted from one of the following:
Referrer
Tick if this refers to
you.
Consultant Clinical Geneticists
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.
Approval Date: Sept 2013
Submitting Laboratory: Manchester RGC
Copyright UKGTN © 2013