Download Townes-Brocks 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: Nottingham RGC
1. Disorder/condition – approved name and
symbol as published on the OMIM
database (alternative names will be listed on the
Approved: Sept 2013
TOWNES-BROCKS SYNDROME; TBS
UKGTN website)
2. OMIM number for disorder/condition
3a. Disorder/condition – please provide, in
laymen’s terms, a brief (2-5 sentences)
description of how the disorder(s) affect
individuals and prognosis.
3b Disorder/condition – if required please
expand on the description of the disorder
provided in answer to Q3a.
4. Disorder/condition – mode of inheritance
5. Gene – approved name(s) and symbol as
published on HGNC database (alternative
107480
Townes-Brocks syndrome is characterised by multiple
birth defects including renal, ear, anal and limb
malformations. The most frequent features are
imperforate anus, dysplastic ears frequently
associated with sensorineural and/or conductive
hearing impairment and thumb malformations. Renal
impairment, congenital heart disease, mental
retardation, foot malformations and genitourinary
malformations can also occur. Prognosis is variable
ranging from mild to severe dependent on the extent
on malformations present.
Autosomal dominant, de novo in ~ 50% of cases
sal-like 1 (Drosophila); SALL1
names will be listed on the UKGTN website)
6a. OMIM number for gene(s)
6b HGNC number for gene(s)
7a. Gene – description(s)
7b. Number of amplicons to provide this
test (molecular) or type of test
(cytogenetic)
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
9a. Technical method(s)
9b If a panel test using NGS please state if
it is a conventional panel or a targeted
exome test.
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?
ii) Does the test include MLPA?
iii) Does this use sanger sequencing or
Next Generation Sequencing (NGS)?
Approval Date: Sept 2013
602218
HGNC:10524
The SALL1 gene contains 3 exons and is located at
16q12.1.
12 amplicons (exon 1 = 1 amplicon, exon 2 = 9
amplicons, exon 3 = 2 amplicons).
Band E.
Missense, Nonsense, Splicing and small
insertion/deletion mutations. Whole exons/multiple
exon deletions/duplications.
Sanger sequencing of exons 1-3 and exon/intron
boundaries. MLPA for whole exon deletions or
duplications (MRC Holland kit P180)
N/A
N/A
Submitting Laboratory: Nottingham RGC
Copyright UKGTN © 2013
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.
11. Validation process
Please explain how this test has been
validated for use in your laboratory or submit
your internal validation documentation
12a. Are you providing this test already?
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.
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
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?
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.
Provided by the laboratory.
The primers have been tested for amplification of
correct region and sequence obtained compared with
reference sequence. Primers have been checked for
SNPs. This laboratory currently performs sequence
analysis of several genes and the same technology is
used for this service. Multiple MLPA kits are already
used within the laboratory. This laboratory participates
in NEQAS and EMQN quality assurance schemes for
sequencing and MLPA-based tests.
No
Yes
31 – full clinical diagnostic setting June 2010-Dec
2012.
1
30 (includes unclassified variants)
Since June 2010.
No
Yes
Dr Mohnish Suri, Consultant Clinical Geneticist
Yes, currently testing for Holt-Oram syndrome (TBX5)
and Okihiro syndrome (SALL4).
16 (based on 2012 figures)
3 (based on 2012 figures, includes family studies for
unclassified variants)
Yes
N/A
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: Nottingham RGC
Copyright UKGTN © 2013
EPIDEMIOLOGY
19a. Estimated prevalence of condition in
the general UK population
Accurate prevalence data is not available for the UK,
partly because the clinical diagnosis of TownesBrocks syndrome is often complicated by overlap with
VACTERL association. A Spanish study by MatinezFrias et al estimated the prevalence as 1:250,000 but
they did not use stringent diagnostic criteria (MartinezFrias et al 1999 An Esp Pediatr. 50;57-60).
19b. Estimated incidence of condition in
the general UK population
Please identify the information on which this is
based
Unknown
20. Estimated gene frequency (Carrier
frequency or allele frequency)
Please identify the information on which this is
based
Unknown
21. Estimated penetrance
Complete penetrance but variable expressivity (from
GeneReviews).
Please identify the information on which this is
based
22. Estimated prevalence of condition in
the population of people that meet the
Testing Criteria.
Unknown.
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: Nottingham RGC
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.
The testing involves bi-directional Sanger sequencing and MLPA. Two SALL1 mutations previously
identified in another European laboratory have been confirmed in our laboratory. The laboratory has
been providing a sequencing and MLPA service for many years for a number of genes including:
BRCA1, BRCA2, TBX5, MSH2, MLH1, MSH6 and are not aware of having missed any mutations. No
issues have been raised in multiple rounds of NEQAS or EMQN.
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).
Clinical sensitivity = In individuals with the classic triad of malformations (ano-rectal, thumb and ear
malformations) characteristic of Townes-Brocks syndrome, sequence analysis of the coding region of
the SALL1 gene is reported to detect mutations in approximately 70% (Kolhase et al 1999,
Am.J.Hum.Genet 64:435-445).
Clinical specificity = 100% (no other distinct phenotypes are associated with SALL1 mutations and
mutations are not seen in unaffected individuals, although variable expressivity means there may be
failure to recognise the disorder).
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).
Based on disease being fully penetrant:
PPV = 100% (although variable phenotype)
NPV = A negative test result does not mean the patient does not have the disorder, they may have a
mutation in a non-coding region of the gene or in another gene such as SALL4, which has clinical
overlap with Townes-Brocks 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. This will be added to the published Testing
Criteria.
Only one gene being tested.
CLINICAL UTILITY
28. How will the test change the management of the patient and/or alter clinical outcome?
Confirmation of the diagnosis of TBS by SALL1 mutation analysis will help to exclude other conditions
that have similar clinical features but are associated with a low sibling and offspring recurrence risk,
such as VACTERL association or with a similar inheritance pattern but a different prognosis, such as
Okihiro syndrome.
This will enable the clinician looking after the patient to provide accurate genetic advice, accurate
information about long-term prognosis and also help with the appropriate management of the patient.
29. Benefits of the test for the patient & other family members
Please provide a summary of the overall benefits of this test.
Finding a mutation in a family member facilitates appropriate genetic counselling and predictive testing
for the at risk family members. Mutation analysis in an affected individual enables testing to be offered
to parents and siblings and enables management planning for the affected individual.
Approval Date: Sept 2013
Submitting Laboratory: Nottingham RGC
Copyright UKGTN © 2013
30. What will be the consequences for patients and family members if this test is not approved?
The following would not be available:
1. Molecular confirmation of the diagnosis of TBS
2. Explanation for the congenital anomalies identified
3. Effective management of patient and appropriate surveillance
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.
There is no alternative method of confirming the diagnosis of TBS.
32. Please describe any specific ethical, legal or social issues with this particular test.
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.
Testing criteria not already available.
We have proposed testing criteria on Page 11, which would have identified all patients in the study
reported by Botzenhart et al. (Hum Mutation 2007; 28: 204-205).
34. List the diagnostic tests/procedures that an index case no longer needs if this
genetic test is available.
Type of test
Costs and type of imaging procedures
Mitomycin C
screen for
Fanconi
anaemia
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
Cost (£)
£250
£250
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/investment
Approval Date: Sept 2013
16 (if diagnostic criteria met would expect 70% of
these to be positive (~11) and 5 to be negative)
£250
£4000
16 x £300 = £4800 (approx 5 expected to be
negative and in need of further testing)
£800 investment
Submitting Laboratory: Nottingham RGC
Copyright UKGTN © 2013
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:
We are providing an example of a patient with ear and thumb malformation where no diagnosis has
been made yet. (This patient has had SALL1 testing which was negative but we don’t have examples of
a clinical diagnosis of Townes-Brock syndrome in our Department).
The 10-month-old boy was referred mainly for unilateral thumb aplasia. There was no family history of
thumb anomalies or other significant medical problems. He was noted to have left thumb aplasia soon
after birth but was also thought to have left-sided Erb palsy in the neonatal period. He failed his
newborn hearing test and a repeat hearing test was due in the near future. His growth parameters were
in the normal range. He had normal eye movements (no evidence of Duane anomaly) and no sign of an
iris coloboma. There was some facial asymmetry at rest but on crying there was reduced movement of
the lower face on the right side. He had small, low set posteriorly rotated ears with bilateral over-folded
helices.
His left thumb was absent but in addition the left upper limb appeared shorter than normal. He held his
left hand in the ‘radial club hand’ posture with radial deviation. There was a cutaneous dimple at the
lower end of ulna. Cardiovascular examination revealed normal heart sounds and no murmurs. There
was no hepatosplenomegaly; he had normal male genitalia and the anal opening was normal. There
was probably mild shortening of the left lower limb as well and cutaneous syndactyly between the 2nd
and 3rd toes on both feet, but more prominent on the left (father also has bilateral cutaneous 2nd/3rd toe
syndactyly). Both patellae were palpable. He had slightly reduced movement at left shoulder and elbow
but normal tone and reflexes in all four limbs. He could reach out and grab objects quite well with his
left hand.
In summary, he was a young boy with a unilateral radial ray abnormality, bilateral dysplastic ears and
possible hearing loss, and a degree of facial asymmetry. His x-rays showed absent left thumb
phalanges and hypoplasia of the middle phalanx of the index and little fingers on the left hand.
The differential diagnosis for his clinical presentation included Townes-Brocks, Okihiro, Holt-Oram,
Fanconi anemia and CHARGE syndromes. For further evidence to support one of the above diagnoses,
he was referred for an ophthalmologic and cardiac evaluation. Features suggesting Townes-Brock
were thumb aplasia and dysplastic ears with possible hearing loss. We arranged for chromosomal
fragility in response to Mitomycin-C (for Fanconi anaemia) and genetic analysis of SALL1 (TownesBrocks syndrome) and SALL4 (Okihiro syndrome) genes. ArrayCGH was also arranged.
All tests to date have been normal or negative, but if he were to have Townes-Brock syndrome, the
diagnosis could have been confirmed by SALL1 analysis. This would have prevented the need for other
genetic tests (arrayCGH, SALL4, TBX5, CHD7) and further clinical evaluation and imaging studies to try
and make the diagnosis. SALL1 testing was activated at the same time as SALL4 testing and array
CGH. Fanconi anaemia testing was performed at a later date. This patient fulfils the proposed testing
criteria for SALL1.
PRE GENETIC TEST COSTS
Type of test
Renal USS, cardiac
echo
Costs and type of imaging procedures
Costs and type of laboratory pathology tests
Costs and type of physiological tests (e.g. ECG)
Approval Date: Sept 2013
Fanconi anaemia
screen, SALL4
ECG
Cost
Similar
to
genetic
therefore
included
£790
Similar
to
genetic
therefore
included
post
cost
not
post
cost
not
Submitting Laboratory: Nottingham RGC
Copyright UKGTN © 2013
Cost and type of other investigations/procedures (e.g. biopsy)
Cost outpatient consultations (genetics and non genetics)
Clinical Genetics x2
Ophthalmology,
Cardiology
Total cost pre genetic test
£340 x 2
£1470
Case example two – post genetic test
We are providing an example of how SALL4 testing improved the patient experience of a couple (this
situation is analogous to SALL1 testing).
A couple were referred for urgent genetic advice in their first pregnancy because the detailed 20 weeks
antenatal scan had shown that the baby had bilateral radial aplasia with unilateral ulnar hypoplasia.
The father of the baby was born with complex congenital heart disease (truncus arteriosus, VSD and
anomalous left anterior descending coronary artery) that required multiple surgeries. He was also born
with bilateral thumb anomalies (right sided thumb hypoplasia and left-sided triphalangeal thumb). On
examination in clinic he was also noted to have bilateral Duane anomaly and poor circulation in his
hands. The differential diagnosis included Holt-Oram syndrome and Okihiro syndrome. Rather than
undertaking testing for Fanconi anaemia or array-CGH on the father, he was tested for mutations in the
TBX5 and SALL4 genes. No mutations were identified in the TBX5 gene but he was found to be
heterozygous for a frameshift mutation in the SALL4 gene, confirming that he was affected with Okihiro
syndrome. The fetus was also tested and found to be heterozygous for the SALL4 mutation identified
in the father.
The couple were informed about the clinical spectrum of SALL4 mutations and they elected to continue
with the pregnancy.
Genetic testing in this family enabled us to confirm the diagnosis of Okihiro syndrome in the father and
the fetus and give the couple detailed advice regarding the clinical problems that could be seen in the
baby (in addition to the forearm bone anomalies already identified on scans). We have also alerted the
Neonatal team so that the baby can be appropriately managed in the neonatal period to avoid missing
the diagnosis of anal stenosis or imperforate anus and mild congenital heart anomalies. The couple are
also now aware of the 50% recurrence risk of Okihiro syndrome in any future pregnancy and they may
consider in vitro fertilisation with pre-implantation genetic diagnosis in the future to avoid the birth of
another affected child.
POST GENETIC TEST COSTS
Type of test
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)
Total cost post genetic test
Cost
£300 (SALL4 testing
also £300)
Similar to pre-genetic
cost
Potential savings on
consultations but not in
all cases. At least
£340x2
£980
37. Estimated savings between two case examples described £490
Approval Date: Sept 2013
Submitting Laboratory: Nottingham RGC
Copyright UKGTN © 2013
UKGTN Testing Criteria
Test name:
Townes-Brocks Syndrome
Approved name and symbol of disorder/condition(s):
Townes-Brocks Syndrome; TBS
Approved name and symbol of gene(s):
sal-like 1 (Drosophila); SALL1
OMIM number(s):
107480
OMIM number(s):
602218
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
Consultant paediatricians
Minimum criteria required for testing to be appropriate as stated in the Gene Dossier:
Criteria
Tick if this patient
meets criteria
At least 2 of the following:
• Imperforate anus or anal stenosis
• Ear malformations (overfolded superior helix, microtia)
• Typical thumb malformations (preaxial polydactyly, triphalangeal
thumbs, hypoplastic thumbs) without shortening of the radius
• Congenital mild to severe sensorineural or conductive hearing loss
• Renal anomalies (agenesis, hypoplasia, polycystic kidneys,
functional impairment with or without structural renal anomalies)
OR At risk family members where familial mutation is known.
Additional Information:
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: Nottingham RGC
Copyright UKGTN © 2013