Download Fanconi Anaemia - UK Genetic Testing Network

Proposal form for the evaluation of a genetic test for NHS Service
Gene Dossier
Test – Disease – Population Triad
Disease – name and description
(please provide any alternative names
you wish listed)
Fanconi Anemia
Estren-Dameshek variant of Fanconi anaemia
VACTERL with hydrocephalus syndrome (VACTERL-H)
(A)-Testing Criteria
OMIM number for disease
227650
Gene – name and description
(please provide any alternative names
you wish listed)
Fanconi anemia, complementation groups A to N
FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF,
FANCG, FANCI, FANCJ, FANCL, FANCM, FANCN
OMIM number for Gene
607139, 300515,227645, 605724, 227646, 600901, 603467,
602956, 611360, 605882, 608111, 609644, 610832
Mutational spectrum for which you Chromosome instability to detect homozygotes
test
Evaluation of spontaneous and diepoxybutane (DEB)-induced
Technical Method (s)
levels of chromosome breakage and sister-chromatid exchange
evaluation
Since 1997, 665 tests performed with 32 positive cases detected,
confirmed clinically.
The use of DEB has been reported as a reliable technique to
Note please explain how this test has detect Fanconi anemia homozygotes/compound heterozygotes.
been validated for use in your
(ref Auerbach AD, Rogatko A and Schroeder-Kurth, Blood 1989
laboratory
73: 391-396)
Yes
Are you providing this test
already? If yes, how many reports 665 reports produced
have you produced?
Validation Process
Please give the number of mutation
positive/negative samples you have
reported
32 positive
633 negative
For how long have you been
providing this service?
Over 10 years
Is there specialised local
Approval Date: Oct 2008
Yes
No
Please provide details
Submitting laboratory: Bristol Cytogentics
clinical/research expertise for this
disease?
Are you testing for other
genes/diseases closely allied to
this one? Please give details
Dr Ruth Newbury Ecob
Consultant Clinical Geneticist
St Michael’s Hospital
Bristol
Clinical expertise in radial ray defects
Dr Colin Steward
Consultant in BMT for Genetic Diseases
BMT Unit
Royal Hospital for Children
Upper Maudlin St
Bristol
BS2 8BJ
Consultant in BMT for Genetic Diseases, runs supraregional
clinic for Fanconi Anaemia at Bristol Royal Hospital for Children
See above – chromosome breakage analysis will detect
homozygotes and compound heterozygotes who may have
mutations in any of the genes listed above
Currently provide 100 annually
Your Activity
We could provide up to 500 tests per annum
How many tests do you (intend to)
provide annually in your laboratory?
Based on experience how many Up to 1000
tests will be required nationally
(UK)?
Our own data (which includes a number of referrals from other UK
Please identify the information on and Ireland labs) and we are aware that a few cytogenetics labs
which this is based
carry out a few such tests per year
Approval Date: Oct 2008
Submitting laboratory: Bristol Cytogentics
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)
Very rare – no overall prevalence quoted, however relatively
common in some ethnic groups:
Ashkenazi Jews 1 in 30000
Black South Africans 1 in 40000
Afrikaans 1 in 20000
(information from OMIM)
From 1 in 77 (Afrikaans), 1 in 87 (Ashkenazi Jews) to 1 in 600
Information from Fanconi Anemia Research Fund inc
Please identify the information on
which this is based
Estimated penetrance
Please identify the information on
which this is based
Close to 100%
Target Population
Thumb deformities/absent thumbs/radial aplasia
Pancytopenia/aplastic anemia
The essential clinical or family history Low birth weight/small stature
features defining the target population MCA suggestive of Fanconi phenotype
must be described.
OR family history of affected sibling (autosomal recessive
condition, or X-linked in VACTERL-H)
(C)-Testing Criteria
Estimated prevalence of disease in
the target population
5 positive cases per 100 referrals
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
Approval Date: Oct 2008

Submitting laboratory: Bristol Cytogentics
Test Characteristics
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.
If a number of genes will be tested,
please include your testing strategy and
data on the expected proportions of
positive results for each part of the
process.
665 tests carried out between 1997 and March 2007, 32 positive
results.
Sensitivity is generally considered to be 100% with DEB testing
(ref. Auerbach et al, as previous).
To our knowledge there have been no positive cases missed
during this 10 year period.
Specificity probably 100%
It may be helpful to include a diagram to
illustrate the testing strategy.
Clinical sensitivity and specificity of
test in target population
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)
Approval Date: Oct 2008
Clinical sensitivity is likely to be over 97%, occasionally
complicated by equivocal test results requiring repeat testing –
some FA cases are mosaics with a normal cell population and
this can occasionally lead to repeat testing.
Clinical specificity is complex- Fanconi anemia testing by
chromosome breakage analysis can be part of the differential
diagnosis of a number of conditions with similar clinical features,
e.g. VATER, Roberts’ syndrome. However there is no evidence
reported of false negative results.
Submitting laboratory: Bristol Cytogentics
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 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). The
denominator in this case is the number
of people with a positive or a negative
test respectively - not the number with
or without the disease. The clinical
validity may be calculated knowing the
sensitivity and the specificity and the
prevalence of the disease in the
population being studied. Positive and
negative predictive values depend
critically on the prevalence of the
disease in the test population
Approval Date: Oct 2008
Positive predictive value is 100%.
Negative predictive value 100%
Chromosome breakage analysis is not considered to be
dependent on the specific Fanconi gene mutation; all
homozygotes/compound heterozygotes will have a positive
result by chromosome breakage analysis and therefore the
cytogenetic method is a global screen that covers all the gene
mutations in FA.
There is no reported evidence of false positive or false negative
diagnoses using the DEB method
Submitting laboratory: Bristol Cytogentics
Clinical utility of test in target
population
(Please refer to Appendix A)
Please provide a full description of
the clinical care pathway for those
individuals undergoing testing. This
should include details of which
medical specialties will be able to
refer for testing.
Patients will be referred mainly by Clinical Geneticists and
occasionally by Haematologists and Foetal Medicine. Clinical
features will be those listed previously; also important to test
siblings of affected family members as they may be potential bone
marrow donors. It is reported that some affected patients may
present with minimal features, e.g. isolated cytopenia, particularly
when detected as part of a family study and that 30% will not have
congenital anomalies.
(B)-Testing Criteria
How will the test add to the
management of the patient or alter
clinical outcome?
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?
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
Positive test will allow appropriate management in terms of drug
treatment and will also identify other at-risk individuals within the
family.
Testing will:
1.Confirm the diagnosis
2.Direct treatment strategies – Fanconi–positive patients are
hypersensitive to alkylating agents and do not tolerate therapeutic
doses of chemotherapy conventionally used in preparation for
bone marrow transplant
3. Patients with aplastic anaemia or cytopenias secondary to
Fanconi may become transfusion independent for many years in
response to small doses of androgens such as oxymetholone.
3. Identify at-risk individuals within the family
4. Allow prenatal diagnosis where required
This application is for cytogenetic analysis, studying the levels of
spontaneous and mutagen-induced chromosome damage.
Molecular genetic analysis for some of the Fanconi genes is
available at Guy’s hospital as a UKGTN service. Chromosome
breakage analysis is not considered to be dependent on the
Are there specific ethical, legal or specific mutation; all homozygotes/compound heterozygotes will
have a positive result by chromosome breakage analysis and
social issues with this test?
therefore the cytogenetic method is a global screen that covers all
the gene mutations in FA.
Please complete the referral pathway diagram on the following page and the testing criteria
form.
Approval Date: Oct 2008
Submitting laboratory: Bristol Cytogentics
Referral Pathway Template –
NOTE: Please use this page as a template. Please expand the test boxes manually as needed.
TARGET POPULATION
Thumb deformities/absent thumbs/radial aplasia
Pancytopenia/aplastic anemia
Low birth weight/small stature
MCA suggestive of Fanconi phenotype
OR family history of affected sibling (autosomal recessive condition or X linked in VACTERLH)
WHAT TYPE AND LEVEL OF PROFESSIONAL OR REFERRER DO YOU ACCEPT
SAMPLES FROM?
Clinical Geneticists
Haematologists
PLEASE PROVIDE DETAILS OF HOW REFERRALS WILL BE ASSESSED FOR
APPROPRIATENESS?
(please complete the test criteria template on the following page)
Clinical features as above – at least two
Other causes of pancytopenia should have been excluded prior to testing
HOW MANY TESTS
DO YOU EXPECT TO
PERFORM
ANNUALLY?
Up to 500
Approval Date: Oct 2008
Submitting laboratory: Bristol Cytogentics
UKGTN Testing criteria
Name of Disease(s): Fanconi Anaemia Complementation groups A to N
Name of gene(s): FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE,
FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, FANCN
Patient name:
Patient postcode:
Name of referrer:
Title/Position:
Referrals will only be accepted from one of the following:
Referrer
Clinical Geneticists
Haematologists
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
Family history (affected sib) of FA
Clinical symptoms
Other causes of pancytopenia excluded
If the sample does not fulfil these criteria and you still feel that testing should be performed
please contact the laboratory to discuss testing of sample.
Approval Date: Oct 2008
Submitting laboratory: Bristol Cytogentics