Download Angioedema, Hereditary, Type I

Proposal form for the evaluation of a genetic test for NHS Service
Gene Dossier
Test – Disease – Population Triad
Disease – name
Hereditary Angioedema [HAE]
OMIM number for disease
106100
Disease – alternative names
please provide any alternative names
you wish listed
Hereditary Angioneurotic Edema; HANE, Deficiency of C1
Esterase Inhibitor
Hereditary Angioedema Type I, Hereditary Angioedema Type II
Disease – please provide a brief
description of the disease
characteristics
Hereditary angioedema (HAE) is a rare single gene disorder
characterised by episodic bouts of well circumscribed, non
urticarial swelling of the subcutaneous, submucosal and
subepithelial tissues. Patients may experience swelling of the
abdomen, face, genitalia and extremities, abdominal pain,
nausea, vomiting, or diarrhoea as well as life-threatening swelling
of the larynx.
The 2 main forms of HAE (Types 1 and 2) are caused by
mutations in the SERPING1 gene. 85% cases of HAE are
classified as Type I and have quantitative and functional
deficiency, whereas in Type II, the C1 esterase inhibitor levels are
normal or elevated, but the protein is nonfunctional. The 2 types
are clinically indistinguishable.
Autosomal dominant. Very rare cases of homozygous deficiency.
SERPING1 (serpin peptidase inhibitor, clade G, member 1)
Disease - mode of inheritance
Gene – name(s)
OMIM number for gene(s)
Gene – alternative names
please provide any alternative names
you wish listed
606860
COMPLEMENT COMPONENT 1 INHIBITOR; C1NH;
C1I; C1INH
Gene – description(s) (including The SERPING1 gene has a chromosomal location of 11q12.1
The 17-kb gene contains 8 exons that include 7 coding exons and
number of amplicons).
a non-coding first exon (Carter et al, 1988). The encoded protein
contains 500 amino acids. It is amplified in 7 amplicons for
sequencing and 6 amplicons for QMPSF.
Mutational spectrum for which you HAE is a disease of extreme allelic heterogeneity. Missense,
test including details of known nonsense, splicing mutations and small deletions/insertions are
common. Large gene rearrangements, including partial gene
common mutations.
deletions and (less frequently) partial duplications, account for
approximately 20% and are thought to be due to unequal
recombination between Alu repeats present within introns.
a) Index case: Fluorescent sequencing of the promoter region, all
Technical Method (s)
codons and flanking regions. Mutations confirmed by sequencing
in the second direction.
If no mutation found, large genomic rearrangements are screened
by Quantitative Multiplex PCR of Short Fluorescent Fragments
[QMPSF]. and confirmed by sequencing across QMPSF primer
sequence
b) Family member: Bi-directional fluorescent sequencing or
QMPSF analysis of relevant gene fragment.
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Approval Date: Sept 2010
Submitting laboratory: Cardiff SAS Porphyria
Copyright UKGTN © 2010
Validation Process
Note: please explain how this test has
been validated for use in your
laboratory
Are you providing this test
already?
Blast analysis of primer sequences
SNP analysis of primers
Optimisation of PCRs
Sequencing of normal individuals and a positive control with
comparison to a reference sequence
Sequencing is used for mutation detection in the laboratory for a
number of genes.
Optimisation of QMPSF following published method. Single and
contiguous exon deletions confirmed by sequencing through
primer regions or using nested primers.
23 reports
If yes, how many reports have you
produced?
Please give the number of mutation
positive/negative samples you have
reported
22 positive, 1 negative. This index case has been subsequently
given an alternative explanation for the angioedema.
For how long have you been
providing this service?
2 years
Is there specialised local
clinical/research expertise for this
disease?
Yes
Please provide details
The Immunology Department delivers the National Paediatric and
adult Primary Immunodeficiency (PID) services for Wales and has
one of the largest cohorts of patients in the UK. This cohort
includes over 40 patients with hereditary angioedema. The
immunology laboratory is the largest in Wales and supports the
diagnosis of PID patients. Clinical services are provided as part of
the Immunology Service as follows:
1) All patients are provided with information about their disorder at
diagnosis. This includes patient support group information and all
Wales PID patients days.
2) Clinical and interpretative advice is available from Dr S Jolles
or Dr P Williams.
3) Outpatient referrals are seen in either Paediatric or Adult
Immunodeficiency Clinics (every 2 weeks and weekly).
4) Inpatient assessment is available through shared care
arrangements with Paediatric Infectious Disease and adult ID
teams with the Department of Medicine.
Are you testing for other
genes/diseases closely allied to
this one? Please give details
There has been a long-standing research interest in both the
treatment and diagnosis of immunodeficiency in the department.
We provide a UKGTN service for sequencing of the IKBKG gene.
The All Wales molecular genetics laboratory also provides a
UKGTN service for and EDA1, EDAR EDARADD and GJB6
(Clouston disease)
Our test repertoire also includes molecular testing, by sequencing
of complement factors C3, C5, C6 C7 C8beta, CFP, MCP and
STAT3.
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Approval Date: Sept 2010
Submitting laboratory: Cardiff SAS Porphyria
Copyright UKGTN © 2010
Index cases: 8
Your Current Activity
If applicable - How many tests do you
Family members where mutation is known: 4
currently provide annually in your
laboratory?
Your
Capacity if Gene Dossier Index cases: 16
approved
Family members where mutation is known: 20
How many tests will you be able to
provide annually in your laboratory if
this gene dossier is approved and
recommended for NHS funding?
Based on experience how many Index cases: 2-5
tests will be required nationally (UK
Family members where mutation is known: 2-5
wide)?
Please identify the information on
It has been estimated that there are approximately 800 HAE
which this is based
patients in the UK and a small proportion (4-5/yr) of these will be
referred for genetic testing. (see below for those cases where
molecular testing is recommended)
We are not aware of any other laboratories offering this service in
National Activity
the UK and are able to provide a national service
(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
There is no data available to give an accurate estimate of the
prevalence of Hereditary Angioedema in the UK population. The
minimal prevalence of HAE in Denmark is approximately 1.41 per
100 000 inhabitants and studies in Spain and Norway suggest
minimal prevalence from 1·09 to 1·51 per 100 000 inhabitants.
Estimation of disease prevalence in American is 1:50000.
Bygum A.Hereditary angio-oedema in Denmark: a nationwide
survey. Br J Dermatol. 1611153-8 2009
Weiler CR Van Dellen RG Genetic Test Indications and
Interpretations in Patients With Hereditary Angioedema. Mayo
Clin Proc 81:958-72 2006
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Approval Date: Sept 2010
Submitting laboratory: Cardiff SAS Porphyria
Copyright UKGTN © 2010
Estimated gene frequency
(Carrier frequency or allele frequency)
Please identify the information on
which this is based
This has not been formally established. HAE is considered to be a
highly penetrant disorder. Approximately 33-50% of cases of HAE
present without a family history but are mostly the result of
sporadic mutation.Therefore gene frequency is likely to be similar
to disease frequency.
Weiler CR Van Dellen RG Genetic Test Indications and
Interpretations in Patients With Hereditary Angioedema. Mayo
Clin Proc 81:958-72 2006
Estimated penetrance
Please identify the information on
which this is based
Pappalardo E et al. Frequent de novo mutations and exon
deletions in the C1inhibitor gene of patients with angioedema.J
Allergy Clin Immunol106:1147-54. 2000
Penetrance is considered to be high in adults, although some
patients have minimal or no symptoms for years before they
become symptomatic.
Pappalardo E et al. Frequent de novo mutations and exon
deletions in the C1inhibitor gene of patients with angioedema.
J Allergy Clin Immunol106:1147-54. 2000
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)
The majority of diagnoses of HAE will be made by biochemical
complement testing (C3, C4, C1INH concentration and functional
C1INH).
The target population for whom molecular testing is of particular
utility are cases of angioedema where the results of biochemical
testing are equivocal.
Positive or negative confirmation of HAE is of equal importance in
providing the appropriate treatment. This group will include:
Population 1
Children under the age of 1, with equivocal biochemistry who
present with angioedema without a family history.
Population 2
At-risk relatives, particularly young children, in families with a
history HAE before onset of clinical symptoms in whom
biochemical testing has not been diagnostic.
Estimated prevalence of disease in
the target population
Population 1
The prevalence of the disease in the target population cannot be
estimated.
Population 2
The prevalence of the disease amongst at-risk relatives is
expected to be 50%
4
Approval Date: Sept 2010
Submitting laboratory: Cardiff SAS Porphyria
Copyright UKGTN © 2010
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
√
Presymptomatic testing
√
Risk Assessment for family members
√
NO
√
Risk Assessment – prenatal testing
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.
The analytical sensitivity of fluorescent sequencing is believed
to be greater than 99%. The analytical sensitivity of QMPSF is
comparable to other methods including MPLA (>95% for
those fragments analysed).
Clinical sensitivity and specificity of
test in target population
Clinical sensitivity
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)
The clinical sensitivity ie the number of patients with clinically
and biochemically defined HAE and have a mutation in the
SERPING1 gene is estimated to be 82-94%. In our laboratory
it is 93%., based on our analyses of index cases. (see above)
Clinical specificity.
Approximately 100%
Many disease causing mutations in HAE are novel missense
mutations (30-40%).
It is not always possible to test the functional significance of
these in the absense of functional studies and/or segregation
analysis. This can reduce test specificity. Predictions can be
made using bioinformatic software, including PolyPhen, by
SERPIN sequence alignments or by reference to the C1Inhibitor gene mutation database. [http://hae.enzim.hu/]
Gösswein T et al Mutational spectrum of the C1INH (SERPING1) gene in
patients with hereditary angioedema. Cytogenet Genome Res. 121:181-8
28. 2008
Pappalardo E et al Mutation screening of C1 inhibitor gene in 108 unrelated
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Approval Date: Sept 2010
Submitting laboratory: Cardiff SAS Porphyria
Copyright UKGTN © 2010
families with hereditary angioedema: functional and structural correlates.Mol
Immunol 45:3536-44. 2008
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).
Positive predictive value
Penetrance is high, however the disease phenotype is very
variable and there are as yet no clear association of genotype
with severity.
Negative predictive value
Family members in whom a familial mutation has been
excluded
are no longer at risk of developing HAE, although the
possibility of sporadic HAE cannot be excluded.
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.
Not applicable
Clinical utility of test in target
population
(Please refer to Appendix A)
Molecular genetic testing of cases of angioedema with a
family history but with equivocal biochemical results and
testing of infants, in whom biochemical testing may be
unreliable, make up the target population.
Please provide a description of the clinical Molecular genetic analysis is an effective way of
care pathway.
confirming the clinical diagnosis and identifying mutation
carriers early on before any clinical manifestation
becomes apparent
How will the test add to the management
of the patient or alter clinical outcome?
The test will allow the introduction of a clear treatment plan in
keeping with HAE consensus guidelines. This aims to reduce
the frequency and severity of attacks using prophylaxis as
well as putting in place a plan for the acute, life-threatening
attacks involving the airway or gastrointestinal tract.
With home therapy patients are provided with home C1
esterase inhibitor supplies which enable them to respond
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Approval Date: Sept 2010
Submitting laboratory: Cardiff SAS Porphyria
Copyright UKGTN © 2010
more rapidly to attacks and plan travel and jobs which might
take them away from their local emergency department.
Increasingly clarity of diagnosis is required to facilitate most
appropriate use expensive treatment interventions.
In hereditary angioedema biochemical testing offers a
diagnostic approach for the majority of cases however in
some the biochemistry results may be equivocal and in the
very young biochemical testing may be unreliable. In these
circumstances molecular testing allows a diagnosis to be
made and hence prophylactic acute and home therapy
management plans can be put into place. The immunology
department at UHW has one of the largest cohorts of
hereditary angioedema places in Wales and a failure to make
a diagnosis has a major impact both on the quality of life of
the patient, the ability to retain a job and of course may lead to
death. We have audited all of the hereditary angioedema
patients in Wales and identified a diagnostic delay of on
average 11.1 years. Prior to the diagnosis being made 1
patient would lose between 30-40 days of work per year and
had all of his teeth extracted as he felt these were causing his
swellings. In addition, many patients may undergo
unnecessary abdominal surgery as the attacks may present
with an acute abdomen and some may have tracheostomies
and be repeatedly treated for an allergic reaction with
adrenaline, antihistamine and steroids. There is a
considerable cost to the NHS of attendance at emergency
departments and admissions to hospital which would be
preventable with appropriate diagnosis and treatment which
would also lead to a reduction in the impact on for example
days of work lost, time lost from school and quality of life.
Failure to diagnose HAE and thus put in place the
prophylactic, acute and home therapy management plans and
immunological follow up to avoid life threatening airway and
gut attacks and improve quality of life.
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.
What are the consequences of not
doing this genetic test.
Commissioners have asked for specific
information to support introduction of
tests.
Utility of test in the NHS
In a couple of sentences explain the utility
of this test for the disease(s)
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
Please describe any specific ethical, legal
or social issues with this particular test?
The emergency treatments available for HAE are costly
(£600-1400/ swelling episode). A positive diagnosis will clarify
the care pathway and the appropriate use of expensive HAE
medication whilst a negative test would require no further
clinical appointments for a presumed diagnosis of HAE.
Biochemical and Immunology investigations demonstrating
low serum C4, low C1INH (Type I) or low functional C1INH
(Type II) are available and will provide a diagnosis in the
majority of cases
However biochemical analysis of C1INH concentration and
function in the very young is unreliable because of the lack of
an appropriate standard range.
None
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Approval Date: Sept 2010
Submitting laboratory: Cardiff SAS Porphyria
Copyright UKGTN © 2010
UKGTN Testing criteria
Name of Disease(s): ANGIOEDEMA, HEREDITARY; HAE (106100)
Name of gene(s): serpin peptidase inhibitor, clade G (C1 inhibitor), member 1;
SERPING1 (606860)
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 Immunologist
Consultant 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
Recurrent non-urticarial angioedema, usually of
gradual onset involving the peripheries, gut or
larynx, usually of gradual onset and lasting 1-5
days and presenting without a family history
AND Equivocal serum C1INH concentration or
function
OR Young children with a family history of
Hereditary Angioedema
AND Equivocal serum C1INH concentration or
function
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.
8
Approval Date: Sept 2010
Submitting laboratory: Cardiff SAS Porphyria
Copyright UKGTN © 2010