Download Genitopatellar syndrome - UK Genetic Testing Network

Proposal form for the evaluation of a genetic test for NHS Service
Gene Dossier/Additional Provider
TEST – DISORDER/CONDITION – POPULATION TRIAD
Submitting laboratory: London South East RGC GSTT
Approved: Sept 2013
1. Disorder/condition – approved name and GENITOPATELLAR SYNDROME; GTPTS
symbol as published on the OMIM
OHDO SYNDROME, SBBYS VARIANT; SBBYSS
database (alternative names will be listed on the
UKGTN website)
2. OMIM number for disorder/condition
Genitopatellar syndrome 606170
Ohdo syndrome 603736
3a. Disorder/condition – please provide, in
laymen’s terms, a brief (2-5 sentences)
description of how the disorder(s) affect
individuals and prognosis.
Genitopatellar syndrome is a rare syndrome
characterised by microcephaly, coarse facial features,
joint contractures of lower limbs, renal anomalies,
cardiac anomalies, genital anomalies, absent patellae
and severe psychomotor delay. Most of these children
die in the first year of life. There are only 20 cases
reported in the medical literature.
Ohdo syndrome is a distinct but overlapping condition
characterised by distinctive facial features, dental
anomalies, low muscle tone, cardiac and renal
anomalies. These individuals also have moderate to
severe psychomotor retardation
3b Disorder/condition – if required please
expand on the description of the disorder
provided in answer to Q3a.
4. Disorder/condition – mode of inheritance
Dominant, de novo mutations for both conditions
5. Gene – approved name(s) and symbol as
published on HGNC database (alternative
K(lysine) acetyltransferase 6B;
KAT6B
names will be listed on the UKGTN website)
6a. OMIM number for gene(s)
605880
6b HGNC number for gene(s)
17582
KAT6B encodes a histone acetyltransferase which is
the catalytic subunit of a tetremeric complex.
Formation of this complex stimulates the acetylation of
E-amino groups on lysine residues which is an
important part of chromatin modelling, a process
which influences gene transcription.
a) KAT6B Panel 1 Seq:
As most mutations are located in exon 18 this
exon will be screened for mutations by unidirectional sequencing of 8 amplicons.
b) KAT6B Panel 2 Seq:
If no mutations are found in exon 18 of KAT6B
then, the remaining exons will be screened for
mutations by uni-directional sequencing of 18
amplicons.
7a. Gene – description(s)
7b. Number of amplicons to provide this
test (molecular) or type of test
(cytogenetic)
Approval Date: Sept 2013
Submitting Laboratory: London South East RGC GSTT
Copyright UKGTN © 2013
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
c) KAT6B Seq:
If requested the whole gene can be screened for
mutations by uni-directional sequencing of all 26
amplicons.
a) KAT6B Panel 1 Seq: Band E
b) KAT6B Panel 2 Seq: Band E
c) KAT6B Seq: Band F
Genitopatellar syndrome:
All mutations reported so far have been in exon 18 of
KAT6B.
Ohdo syndrome:
Majority of mutations are in exon 18, others have been
identified in exons 3, 8, 15.
9a. Technical method(s)
Mutation analysis will be performed by uni-directional
fluorescent Sanger sequencing. All potential
pathogenic variants/mutations will be confirmed using
a fresh DNA dilution by bi-directional Sanger
sequencing.
(see 7b for workflow)
9b If a panel test using NGS please state if
it is a conventional panel or a targeted
exome test.
N/A
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?
N/A
ii) Does the test include MLPA?
iii) Does this use sanger sequencing or
Next Generation Sequencing (NGS)?
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.
No, by the DNA Laboratory (GSTS Pathology)
11. Validation process
Please explain how this test has been
validated for use in your laboratory or submit
your internal validation documentation
Since the discovery by our research group through
whole exome sequencing that mutations in exon 18 of
KAT6B underlie Genitopatellar/Ohdo syndrome, we
have tested fivesamples on a research basis. Eight
pairs of primers were designed to generate eight
overlapping amplicons for exon 18, which were then
screened for mutations by fluorescent Sanger
sequencing.
(ASHG 90, 290–294, February 10, 2012)
12a. Are you providing this test already?
Approval Date: Sept 2013
No
Yes
Submitting Laboratory: London South East RGC GSTT
Copyright UKGTN © 2013
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.
Mutations identified in 5 samples report in ASHG 90,
290–294, February 10, 2012
c.3680_3695del (p.Asp1227GlufsX11
c.3769_3772delTCTA (p.Lys1258GlyfsX13) (Found in two
patients)
c.3877A>T (p.Lys1293X)
c.3773dup (p.Trp1259ValfsX12)
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?
14b. If yes, please provide details
No
15. Are you testing for other
genes/disorders/conditions closely allied
to this one? Please give details
16. Based on experience what will be the
national (UK wide) activity, per annum, for:
16a. Index cases
16b. Family members where mutation is
known
17a. Does the laboratory have capacity to
provide the expected national activity?
Yes
Dr Charu Deshpande is a Clinical Geneticist who has
special interest in Genitopatellar/Ohdo syndrome. She
was also part of the research group which included
the Clinical Genetics, Guy’s Hospital and Division of
Genetics and Molecular Medicine, King’s College
London School of Medicine who discovered the
KAT6B gene
Not at present
Approximately 15 a year (based on numbers required
for GTPTS. Manchester provides activity numbers
based on Ohdo syndrome)
30
Yes
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.
Approval Date: Sept 2013
N/A
Submitting Laboratory: London South East RGC GSTT
Copyright UKGTN © 2013
EPIDEMIOLOGY
19a. Estimated prevalence of condition in
the general UK population
Not available – 20 cases of GTPTS in literature.
19b. Estimated incidence of condition in
the general UK population
Please identify the information on which this is
based
Not available – 20 cases of GTPTS in literature.
20. Estimated gene frequency (Carrier
frequency or allele frequency)
Please identify the information on which this is
based
N/A
KAT6B mutations are de novo mutations.
As reported in 3 separate research studies.
21. Estimated penetrance
Please identify the information on which this is
based
100% based on current data.
22. Estimated prevalence of condition in
the population of people that meet the
Testing Criteria.
Almost 100%.
INTENDED USE
23. 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
No
Prognosis & management
Yes
No
(n/a for panel tests)
Yes
No
Carrier testing for family members (n/a for panel tests)
Yes
No
Prenatal testing
(n/a for panel tests)
Yes
No
Approval Date: Sept 2013
Submitting Laboratory: London South East RGC GSTT
Copyright UKGTN © 2013
Presymptomatic testing
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.
Unidirectional sequencing coupled with the use of Mutation Surveyor® software has an analytical
sensitivity and specificity of >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).
The clinical sensitivity will >99%
The clinical specificity will >99%
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).
The PPV will approach 100%.
The NPV will approach 100%.
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.
N/A
CLINICAL UTILITY
28. How will the test change the management of the patient and/or alter clinical outcome?
It will prevent unnecessary investigations and allow planning of appropriate care pathway. Parents and
physicians would be able to discuss supportive care rather than aggressive management for GTPTS
patients.
For the Ohdo syndrome patients, it will allow appropriate surveillance – cardiac, thyroid function tests
and developmental assessments. Early definitive diagnosis will allow prompt institution of management
and optimise outcome.
29. Benefits of the test for the patient & other family members Please provide a summary of the overall
benefits of this test.
GTPTS patients are often very unwell in the first year of life. Having a definitive diagnosis would assist
the parents to understand the poor prognosis. This will mean that they are able to provide the best
possible supportive care for the child and avoid unnecessary hospital admissions and procedures. This
also allows accurate genetic counselling and accurate prenatal diagnosis in future pregnancies.
For patients with SBB variant of Ohdo syndrome, it allows parents, carers and school to understand the
condition. This will help the parents to understand the need for additional medical surveillance and also
help provide additional support for the child’s developmental progress.
30. What will be the consequences for patients and family members if this test is not approved?
It is not possible to be certain of the clinical diagnosis on clinical assessments alone. This is particularly
difficult in young children, especially in the first year of life. It is at this stage a definitive diagnosis would
be most helpful. Confirmation of diagnosis by KAT6B testing will allow planning for appropriate medical
surveillance, supportive care and family support without the need for multiple hospital visits and
invasive investigations.
Unable to make informed reproductive decisions.
Approval Date: Sept 2013
Submitting Laboratory: London South East RGC GSTT
Copyright UKGTN © 2013
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.
No.
32. Please describe any specific ethical, legal or social issues with this particular test.
None we are aware of
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.
Example in box 36: n/a to additional provider applications
Costs and type of imaging procedures
Costs and types of laboratory pathology tests
(other than molecular/cyto genetic test proposed in this gene
dossier)
Costs and types of physiological tests (e.g. ECG)
Cost and types of other investigations/procedures (e.g. biopsy)
Total cost tests/procedures no longer required
Type of test
MRI brain
Full
skeletal
survey (only lower
limb
images
would be needed)
Cost (£)
£1100
£335
EEG
Muscle biopsy
£295
£1000
£2,730
35. 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
Cost to provide tests for index cases if the
genetic test in this gene dossier was not
available (see Q34)
Total annual costs pre genetic test
Total annual costs to provide genetic test
Total savings
~15
£2730
15 x £2730 = £40,950
£6501 as per Financial section
£40950 – 6501 = £34,449 cost savings
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
The patient was the second child in the family. There was a period of infertility prior to conception of the
proband and the parents were very anxious. She was noted to have unusual facial features at birth and
contractures of the hips, knees and ankles. In view of this, she had a brain MRI scan, skeletal survey
and kidney ultrasound on day 1 of life and these were normal. She was referred to a specialist unit for
neurological evaluation in view of the contractures.
Approval Date: Sept 2013
Submitting Laboratory: London South East RGC GSTT
Copyright UKGTN © 2013
During the neonatal period, she had extensive investigations including a muscle and skin biopsy. These
yielded normal results and she was discharged to the local hospital as the parents were finding the
journey to the specialist centre very difficult. She was readmitted at few weeks of age as she was not
feeding well. The weight gain was poor and her mother expressed concerns about the infant’s ability to
swallow. After multiple visits to the hospital, the child was eventually fitted with a naso-jejunal tube and
then gastrostomy. The child developed seizures at 6 months of age and was attending the neurology
clinic. At 6 months, an ultrasound scan of the knees confirmed absent patellae and she was confirmed
to have Genitopatellar syndrome.
The parents were seen in the genetics clinic and counselled regarding the poor prognosis for
developmental progress and long term health issues. The parents were devastated. They required
extensive psychosocial support over the coming months and the parents finally came to terms with the
diagnosis when the child was a year old. The parents were then able to seek appropriate support from
the local community paediatrics services and seek access to respite care.
The child started developing apneas and these were difficult to manage. Sadly, she passed away on
Christmas Eve following a prolonged apnea.
Following the confirmation of the clinical diagnosis, her mother requested genetic tests to confirm this
diagnosis. She was also very upset about the high risk of recurrence in future pregnancies as this was
presumed to be an autosomal recessive disorder.
Since the gene was unknown at that time, we proceeded to try and identify the causative gene. Sadly,
we were able to do so after the child had passed away. We met the family subsequently to inform them
of the results.
Her parents were pleased to have a definitive diagnosis at last, know that the risk to their older child
and future children was negligible and they felt able to consider further children. They had also found it
helpful to know the prognosis and the course of the condition. Her mother took time away from work to
be able to be with her child. However, as it was a clinical diagnosis, they were hoping the outlook was
not as bleak as predicted. Although it was very upsetting, they were grateful they were able to keep
their child comfortable and enjoy as much time as possible with her.
If we had a definitive diagnostic test to offer, we may have been able to institute appropriate safe
feeding early. Also, we may have had an opportunity to involve the palliative care team at a much
earlier stage to support the family.
PRE GENETIC TEST COSTS
Costs and type of imaging procedures
Costs and type of laboratory pathology tests
Costs and type of physiological tests (e.g. ECG)
Cost and type of other investigations/procedures (e.g. biopsy)
Cost outpatient consultations (genetics and non genetics)
Total cost pre genetic test
Approval Date: Sept 2013
Type of test
Skeletal survey
Neonatal MRI Scan
Abdominal
ultrasound scan
Patellar scan
Cost
£335
£1000
EEG (X2)
Muscle biopsy
Gastrostomy
Paediatrics
Feeding clinic (X6)
Neurology ( X4)
Respiratory team
Community
Paediatrics
Genetics (X3)
£590
£1000
£4368
£150
£300
£600
£150
£100
£227
£157
£900
£9,977
Submitting Laboratory: London South East RGC GSTT
Copyright UKGTN © 2013
Case example two – post genetic test
This is would be the simulated cost for a patient who is suspected to be affected with Genitopatellar
syndrome (GTPTS) / Ohdo syndrome (Say-Barber-Biesecker variant).
POST GENETIC TEST COSTS
Costs and type of imaging procedures
Costs and types laboratory pathology tests
(other than molecular/cyto genetic proposed in this gene
dossier)
Cost of genetic test proposing in this gene dossier
Costs and type of physiological tests (e.g. ECG)
Cost and type of other investigations/procedures (e.g. biopsy)
Cost outpatient consultations (genetics and non genetics)
Type of test
As above
Cost
£1,719
KAT6B Panel 1
£301 (excluding
DNA extraction)
Paediatrics
Genetics (x2)
Community
Paediatrics
Feeding
clinic
(X3)
£150
£600
£100
Total cost post genetic test
£3020
37. Estimated savings between two case examples described
Approval Date: Sept 2013
£150
£ 6957
Submitting Laboratory: London South East RGC GSTT
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
Ohio Syndrome
Approved name and symbol of gene(s):
K(lysine) acetyltransferase 6B; KAT6B
OMIM number(s):
603736
249620
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: London South East RGC GSTT
Copyright UKGTN © 2013
UKGTN Testing Criteria
Test name:
Genitopatellar and Ohdo Syndrome
Approved name and symbol of disease/condition(s):
Genitopatellar Syndrome
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: London South East RGC GSTT
Copyright UKGTN © 2013