Download 1q21.1 200kb deletion - UK Genetic Testing Network

Proposal form for the evaluation of a genetic test for NHS Service
Gene Dossier
Test – Disease – Population Triad
Disease – name
TAR SYNDROME
OMIM number for disease
274000
Disease – alternative names
please provide any alternative names
you wish listed
CHROMOSOME 1q21.1 200KB DELETION SYNDROME,
THROMBOCYTOPENIA-ABSENTRADIUSSYNDROME
TETRAPHOCOMELIA-THROMBOCYTOPENIA SYNDROME,
INCLUDED
Disease – please provide a brief
description of the disease
characteristics
Clinically well characterised malformation syndrome. Typical
features include hypomegakaryocytic thrombocytopenia and
bilateral absence of the radius in the presence of both thumbs.
Additional skeletal features include shortening, and less
commonly, aplasia of the ulna and/or humerus. Lower limb
involvement present to a lesser extend.
TAR is multiple malformation syndrome and extra skeletal
manifestations comprise cardiac abnormalities such as tetralogy
of Fallot, and abnormalities of the genitourinary tract. In addition
cow’s mlk intolerance appears to be relatively common and may
lead to eosinophilia.
Genetic basis is currently unknown. 200kb deletion at 1q21.1 is
necessary but not sufficient to cause the phenotype, additional
modifying factors have been proposed. In approx 75% of cases
the deletion is inherited from one parent, 25% cases are sporadic.
200kb deletion at 1q21.1 encompassing the genes;HFE2, TXNIP,
PLOR3GL, ANKRD34A, LIX1L, RBM8A, GNRHR2, PEX11B,
ITGA10, ANKRD35, PIAS3, NUDT1. This region is deleted in all
patients. Klopocki et al 2007 report that 28/20 TAR syndrome
individuals have a larger 500kb deletion extending towards the
telomere including and additional 5 genes.
Both TAR syndrome associated deletions are distinct and
separate from the 1q21.1 deletion/duplication syndromes.
Disease - mode of inheritance
Gene – name(s)
OMIM number for gene(s)
Gene – alternative names
please provide any alternative names
you wish listed
Klopocki E, Schulze H, Strauss G, Ott CE, Hall J, Trotier F,
Fleischhauer S, Greenhalgh L, Newbury-Ecob RA, Neumann LM,
Habenicht R, König R, Seemanova E, Megarbane A, Ropers HH,
Ullmann R, Horn D, Mundlos S. Complex Inheritance Pattern
Resembling Autosomal Recessive Inheritance Involving a
Microdeletion in TAR syndrome. Am J Hum Genet. 2007; 80:
232–40.
n/a
n/a
Gene – description(s) (including 200 kb deletion at 1q21.1 encompassing 11 genes.
number of amplicons).
1
Approval Date: Sept 2010
Submitting laboratory: Bristol Genetics Laboratory
Copyright UKGTN © 2010
Mutational spectrum for which you 200kb deletion at 1q21.1
test including details of known
common mutations.
Technical Method (s)
Validation Process
Note: please explain how this test has
been validated for use in your
laboratory
Are you providing this test
already?
Multiplex Ligation dependant probe amplification ( MLPA ).
This technique is currently employed at BGL for many routine
diagnostic assays using commercial kits available form MRC
Holland. An in-house MLPA was successfully developed in 2009
for Axenfeld Reigers syndrome using MRC-Holland p300-A1
probe mix.
The 1q21.1 assay contains 3 probes mapping to the 200kb
deleted region, flanking probes ( within the 500 kb deletion and
also flanking this ) and control probes from other non-polymorphic
regions of the genome. Routine statistical analysis is applied
using GeneMarker software.
This included the following steps:
• design MLPA probes for use with the MRC-Holland p300A1 probe mix;
• Check primers for SNPs using ‘primer3’ and ‘SNP check
Manchester NGRL’ online software
• Set-up the dosage analysis and optimise the MLPA assay
using 5 ‘Normal controls’ commercially available from
Health Protection Agency Culture Collections and 28
positive cases banked as extracted DNA at the laboratory
please provide details ( collected at BGL as part of
research study ) and confirmed as positive by qPCR
testing at the research laboratory of Dr Stefan Mundlos
and Dr Eva Klopocki in Berlin.
No
Validation of assay ongoing. There are 28 families referred for
TAR syndrome testing stored at BGL. 20/28 have a confirmed
If yes, how many reports have you
deletion of 1q21.1 as tested by Dr E Klopocki by quantitative PCR
produced?
testing as a research study. In 6/28 families DNA was not
Please give the number of mutation available from the index case. 2/28 families do not have the 1q
positive/negative samples you have deletion, but other chromosome anomalies have been detected.
reported
The deletion is present one parent in 8/20 families.
MLPA validation is underway at BGL on 28 positive DNA samples
and normal controls.
No laboratory diagnostic test yet available.
For how long have you been
providing this service?
Is there specialised local
clinical/research expertise for this
disease?
Are you testing for other
genes/diseases closely allied to
this one? Please give details
Yes
Please provide details
Dr Ruth Newbury-Ecob is a clinical geneticist with research
expertise in this area. Previous collaborations include the
Klopocki Am J Hum Genet 2007 TAR syndrome paper.
Roberts syndrome (MIM268300) and Fanconi Anaemia (MIM
227650) UKGTN providers. ASD dossier in preparation. Ruth
Newbury-Ecob is clinical expert in Holt-Oram Syndrome.
None, test validation ongoing.
Your Current Activity
If applicable - How many tests do you
currently provide annually in your
laboratory?
2
Approval Date: Sept 2010
Submitting laboratory: Bristol Genetics Laboratory
Copyright UKGTN © 2010
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?
Index cases:
Capacity will be available to meet demand for UK and abroad.
Test is straightforward.
Family members where mutation is known:
Based on experience how many Index cases: UK cases 30 per annum
tests will be required nationally (UK Family members where mutation is known 30 per annum
wide)?
Please identify the information on
which this is based
We are not aware of other labs providing this activity, we are able
National Activity
to provide for UK cases and abroad.
(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 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
Estimated prevalence of disease in
the general UK population
Please identify the information on
which this is based
Estimated gene frequency
(Carrier frequency or allele frequency)
0.42 cases per 100,000 live births in Spain.
The prevalence of TAR syndrome is generally estimated at
0.5:100,000 to 1:100,000
No accurate data available.
Please identify the information on
which this is based
Estimated penetrance
Please identify the information on
which this is based
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)
Other unknown factors associated with expression of disease
phenotype.
1. Diagnostic testing. Patients with a clinical diagnosis of
TAR syndrome with bilateral absence of the radii with the
presence of both thumbs and thrombocytopenia (<50
platelets/nL), generally transient. Molecular confirmation of
diagnosis in pregancies where radial anomalies are
identified on routine ultrasound.
3
Approval Date: Sept 2010
Submitting laboratory: Bristol Genetics Laboratory
Copyright UKGTN © 2010
2. At risk testing. Unaffected parents of patients with a
positive molecular diagnosis of TAR ( 75% cases are
inherited ) to establish recurrence risks. Sibs and extended
relatives of patients where patents are carrying the 200kb
deletion. Offspring of a patient with a molecular diagnosis
of TAR syndrome.
3. Prenatal testing. Prenatal diagnosis for pregancies at
increased risk of TAR syndrome, coupled with ultrasound
evaluation of fetal limbs and heart.
Estimated prevalence of disease in
the target population
100% of patients with TAR syndromes have the 200kb deletion at
1q21.1.
75% cases this will be carried by one parent who will be
unaffected although radiographs of the limbs are recommended
as minor limb involvement in some has been reported.
Risk of inheriting the deletion is 50%, prenatal diagnosis must be
accompanied by ultrasound examination to evaluate the limbs, as
the deletion alone is not sufficient for the diagnosis of TAR
syndrome.
Intended Use (Please use the questions in Annex A to inform your answers)
Please tick the relevant clinical purpose of testing
YES
Diagnosis
√
Treatment
√
Prognosis & Management
√
NO
Presymptomatic testing
Risk Assessment for family members
√
Risk Assessment – prenatal testing
√
4
Approval Date: Sept 2010
Submitting laboratory: Bristol Genetics Laboratory
Copyright UKGTN © 2010
Test Characteristics
An a lytic a l s e n s itivity a n d s p e c ificity
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.
Validated MLPA will be 100% sensitive for detecting the 200kb
deletion event. It will not inform over the extent of the deletion
beyond this region, but that is not currently considered clinically
relevant.
Clinical sensitivity and specificity of
test in target population
Klopocki et al Am J Hum Genet 2007 80 232-240 indicate that
30/30 unrelated TAR affected individuals have this 200kb
deletion at 1q21.1. Clinical sensitivity 100%.
This deletion is sufficient to confirm the diagnosis in individuals
with bilateral absence of the radius and presence of thumbs.
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)
75% cases are inherited from an unaffected parent indication
that haploinsufficiency is not sufficient for the phenotype and a
second unknown mutant gene is required.
Family testing can identify those at risk. This should be
supported by ultrasound examination to evaluate limbs in
prenatal diagnosis, and radiographs of limbs should be
considered in parents/relatives carrying the deletion as minor
limb involvement in some has been reported.
Negative predictive value 100%.
In the presence of symptoms positive predictive value 100%.
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 expected 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.
Family testing required ultrasound/radiograph support, but
identified those at risk.
Diagnostic/exclusion/family/prenatal tests for 1q21.1 deletion
only.
5
Approval Date: Sept 2010
Submitting laboratory: Bristol Genetics Laboratory
Copyright UKGTN © 2010
Clinical utility of test in target
population
(Please refer to Appendix A)
Molecular confirmation of a clinical diagnosis provided definitive
diagnosis and facilitates family testing allowing the identification of
at risk relatives, recurrence risks and prenatal diagnosis. This is
particularly important as many carrier parents are asymptomatic.
Provides reassurance to those who do not carry the deletion.
Please provide a description of the
Prenatal diagnosis is possible with confirmation by ultrasound.
clinical care pathway.
How will the test add to the
management of the patient or alter
clinical outcome?
Confirmation of diagnosis will inform on patient prognosis and aid
in patient management and treatment. Allows monitoring and
treatment to be performed sooner e.g. platelet transfusion for
thrombocytopenia,
platelet
count
surveillance.
Enables
determination of recurrent risk for future pregnancies. High risk
where one parent carries deletion. Very low if neither parent
carries deletion.
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.
Early targeting and management.
Defining those at risk.
Treatment as above.
What are the consequences of not
doing this genetic test.
Commissioners have asked for
specific information to support
introduction of tests.
Those at risk of having TAR syndrome affected offspring will not
be identified or appropriately supported. Babies could be born
with a severe disability. Incorrect diagnosis with incorrect genetic
information
Utility of test in the NHS
In a couple of sentences explain the
utility of this test for the disease(s)
Definitive diagnosis supporting early monitoring, treatment and
orthopaedic intervention.
Identification of those at risk and reassurance to those not at risk.
Prenatal diagnosis made possible.
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 alternative test available. Ultrasound and radiography is not
specific.
Deletion can be detected as part of aCGH screen but this is a nonspecific test
Please describe any specific ethical,
legal or social issues with this
particular test?
Patients with TAR have long term health care needs. Accurate
diagnosis will contribute to good clinical management and
appropriate educational support in the case of children.
6
Approval Date: Sept 2010
Submitting laboratory: Bristol Genetics Laboratory
Copyright UKGTN © 2010
UKGTN Testing criteria
Name of Disease(s):
CHROMOSOME 1q21.1 DELETION SYNDROME, 200-KB (274000)
Name of gene(s): 200kb deletion 1q21.1
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
Clinical Geneticist
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
Bilateral absence of the radii with the presence of
both thumbs and thrombocytopenia (<50
platelets/nL)
OR radial anomalies identified on a routine
ultrasound evaluation with thumbs present
Family testing for parents of cases with molecular
confirmation of diagnosis, and testing of relatives
where parents are carrying the 200kb deletion
Prenatal diagnosis for pregnancies at increased
risk in combination with ultrasound evaluation of
limbs.
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.
7
Approval Date: Sept 2010
Submitting laboratory: Bristol Genetics Laboratory
Copyright UKGTN © 2010