Download FGFR3-Related Skeletal Dysplasias Panel Test (NIPD)

 Proposal form for the evaluation of a genetic test for NHS Service
Gene Dossier/Additional Provider
TEST – DISORDER/CONDITION – POPULATION TRIAD
Submitting laboratory: London North East RGC GOSH
1. Disorder/condition – approved name and See appendix 1
symbol as published on the OMIM
database (alternative names will be listed on the
Approved:
Sept 13
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.
See appendix 1
Several skeletal disorders are caused by de novo
mutations in the FGFR3 gene. Accurate diagnosis of
skeletal dysplasias before birth is challenging as many
arise de novo and molecular diagnosis is required for
definitive diagnosis and accurate parental counselling.
Until recently this required invasive testing, but with
technological advances this is now possible using cell
free fetal DNA (cffDNA) in maternal blood.
Achondroplasia is characterised by abnormal bone
growth that results in short stature with
disproportionately short arms and legs plus
characteristic facial features with frontal bossing.
Thanatophoric dysplasia is a lethal skeletal dysplasia.
All affected cases die from respiratory failure within
hours of birth. An affected fetus will have short long
bones, a small chest, macrocephaly, frontal bossing
and short fingers.
In achondroplasia, additional presentations include
mid-face hypoplasia, limitation of elbow extension and
trident hand. In infancy, hypotonia is typical, and
acquisition of developmental motor milestones can be
delayed. Intelligence and life span are usually normal,
although compression of the spinal cord and/or upper
airway obstruction increases the risk of death in
infancy.
TD cases are all affected with pulmonary hypoplasia,
but in addition are classified into subtypes based on
the presence of curved as opposed to straight femurs.
TD1 cases have curved, short femurs with or without
craniosynostosis. TD2 cases have straight, relatively
long femurs with severe craniosynostosis.
4. Disorder/condition – mode of inheritance
Autosomal dominant
5. Gene – approved name(s) and symbol as
published on HGNC database (alternative
Fibroblast Growth Factor Receptor 3 (FGFR3)
names will be listed on the UKGTN website)
6a. OMIM number for gene(s)
134934
6b HGNC number for gene(s)
HGNC:3690
7a. Gene – description(s)
The fibroblast growth factor receptor 3 (FGFR3) is
located on chromosome 4p16.3
Approval date: Sept 13
Copyright UKGTN © 2013
Submitting laboratory: London North East RGC GOSH
1
It consists of 19 exons spanning 16.5 kb
7b. Number of amplicons to provide this
test (molecular) or type of test
(cytogenetic)
5
7c. GenU band that this test is assigned to
for index case testing
Not currently available for NGS assay, but we would
estimate band E for this targeted panel.
8. Mutational spectrum for which you test
including details of known common
mutations
18 mutations in FGFR3 causing achondroplasia or
thanatophoric dysplasia are available on the targeted
panel for NIPD:
Achondroplasia:
c.1138G>A mutation (p.Gly380Arg) (98% of cases)
c.1138G>C (p.Gly380Arg)
c.1123G>T (p.Gly375Cys)
c.1130T>G (p.Leu377Arg)
Thanatophoric dysplasia:
TD1:
c.742C>T (p.Arg248Cys) accounts for approximately
55% of cases
c.1118A>G (p.Tyr373Cys) – 24% of TD1 mutations
c.746C>G (p.Ser249Cys) – 6% of TD1 mutations
c.1108G>T (p.Gly370Cys)
c.1111A>T (p.Ser371Cys)
c.2419T>G (p.*807Glyext*102)
c.2419T>A (p.*807Argext*102)
c.2420G>T (p.*807Leuext*102)
c.2420G>C (p.*807Serext*102)
c.2421A>T (p.*807Cysext*102)
c.2421A>C (p.*807Cysext*102)
c.2421A>G (p.*807Trpext*102)
TD2: A single mutation, c.1948A>G (p.Lys650Glu),
has been reported in all cases to date.
Severe achondroplasia with developmental delay
and acanthosis nigricans (SADDAN):
c.1949A>T (p.Lys650Met)
A further 11 common FGFR3 mutations are included
that lead to a milder presentation of craniosynostosis
or skeletal dysplasia (hypochondroplasia). These are
for potential postnatal diagnosis and can be excluded
for NIPD referrals.
Craniosynostosis / Muenke syndrome:
c.749C>G (p.Pro250Arg)
c.749C>T (p.Pro250Leu)
Hypochondroplasia:
c.1142T>A (p.Val381Glu)
c.1619A>C (p.Asn540Thr)
c.1619A>G (p.Asn540Ser)
c.1620C>G (p.Asn540Lys)
c.1620C>A (p.Asn540Lys)
c.1948A>C (p.Lys650Gln)
c.1950G>C (p.Lys650Asn)
Approval date: Sept 13
Copyright UKGTN © 2013
Submitting laboratory: London North East RGC GOSH
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c.1950G>T (p.Lys650Asn)
9a. Technical method(s)
9b If a panel test using NGS please state if
it is a conventional panel or a targeted
exome test.
Hypochondroplasia plus acanthosis nigricans:
c.1949A>C (p.Lys650Thr)
cffDNA extraction from maternal plasma
PCR to amplify 5 amplicons of FGFR3 covering 29
known mutations, followed by NGS (Illumina MiSeq)
Conventional Panel
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?
Targeted amplicons to cover 29 recurrent FGFR3
mutations
ii) Does the test include MLPA?
No
iii) Does this use sanger sequencing or
Next Generation Sequencing (NGS)?
NGS
iv) If NGS is used, does the lab adhere to
the Practice Guidelines for NGS?
Yes, where applicable to NIPD.
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.
Provided by the lab
11. Validation process
Please explain how this test has been
validated for use in your laboratory or submit
your internal validation documentation
1) Five normal control cffDNA samples and two
normal gDNA samples were tested using all
five amplicons in the FGFR3 NGS panel to
confirm that only wild type sequences were
seen.
2) To obtain material for validation, maternal
blood for cffDNA analysis was requested by
the laboratory whenever a sample from an
invasive prenatal test for FGFR3 was received.
3) Positive control gDNAs from CVS for
c.1138G>A
(achondroplasia),
c.1620C>G
(hypochondroplasia), c.1118A>G, c.2421A>G,
c.2419T>A, c.2419T>G (type I TD), and
c.1948A>G (type II TD) were run to ensure that
the panel was able to detect the expected
mutations.
4) Six cffDNA samples that had been tested
previously for TD using PCR-RED and dPCR
(for c.742C>T and c.1948A>G mutations) were
examined using the NGS panel for skeletal
dysplasias and results were shown to be
concordant. In addition one further mutation
(c.1118A>G) was identified in a fetus with a
definite ultrasound diagnosis (subsequently
confirmed by postnatal radiology) of TD.
5) The NGS panel was run in parallel with the
Approval date: Sept 13
Copyright UKGTN © 2013
Submitting laboratory: London North East RGC GOSH
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12a. Are you providing this test already?
ACH restriction digest test for 9 diagnostic
samples.
6) The NGS panel was run in parallel with the TD
c.742C>T PCR restriction digest for 2
diagnostic samples.
No
Yes
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.
10 diagnostic reports for ACH (two tested for risk of
recurrence due to germline mosaicism). Testing
carried out in parallel with restriction digest assay.
4 reports for TD (tested on a research basis and
results confirmed on fetal blood)
12c. Number of reports mutation positive
3 ACH; 2TD1
12d. Number of reports mutation negative
7 ACH; 2 TD
13. For how long have you been providing
this service?
9 months
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.
No
Yes
Dr Jane Hurst, Clinical unit lead for the North East
Thames Regional Genetics Service.
Professor Lyn Chitty, PI RAPID project - GOSH
Yes.
Sex determination using cffDNA.
Achondroplasia and Thanatophoric dysplasia testing
using PCR and restriction enzyme digest on cffDNA.
FGFR3-related skeletal dysplasia testing of
CVS/Amniocentesis samples or blood samples postdelivery.
ACH – 40 & TD – 10
This uses NIPD where we look for recurrence due to
germline mosaicism in subsequent pregnancies
ACH – 8 & TD - 2
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.
N/A
Approval date: Sept 13
Copyright UKGTN © 2013
Submitting laboratory: London North East RGC GOSH
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EPIDEMIOLOGY
19a. Estimated prevalence of condition in
the general UK population
Thanatophoric dysplasia (TD) is lethal in the neonatal
period it is not prevalent in the population.
Achondroplasia : 0.36-0.60 per 10 000 individuals
Waller, D. K., Correa, A., Vo, T. M., Wang, Y., Hobbs, C.,
Langlois, P. H., Pearson, K., Romitti, P. A., Shaw, G. M., Hecht, J.
T. The population-based prevalence of Achondroplasia and
thanatophoric dysplasia in selected regions of the US. Am. J. Med.
Genet. 146A: 2385-2389, 2008.
19b. Estimated incidence of condition in
the general UK population
Please identify the information on which this is
based
Achondroplasia is the most common non-lethal
skeletal dysplasia, and has an incidence of 5-15 per
100,000 live births.
Thanatophoric dysplasia (TD) is the most common
lethal skeletal dysplasia with an incidence of 2-3 per
100,000 births.
Waller, D. K., Correa, A., Vo, T. M., Wang, Y., Hobbs, C.,
Langlois, P. H., Pearson, K., Romitti, P. A., Shaw, G. M., Hecht, J.
T. The population-based prevalence of Achondroplasia and
thanatophoric dysplasia in selected regions of the US. Am. J. Med.
Genet. 146A: 2385-2389, 2008.
20. Estimated gene frequency (Carrier
frequency or allele frequency)
Please identify the information on which this is
based
N/A
21. Estimated penetrance
Please identify the information on which this is
based
100%
22. Estimated prevalence of condition in
the population of people that meet the
Testing Criteria.
1. Where a previous pregnancy has been confirmed
to have an FGFR3-related skeletal dysplasia there
is a small risk of recurrence due to germline
mosaicism.
2. Population based risk of a de novo mutation. In
these cases songraphic findings will suggest a
diagnosis of FGFR3-related skeletal dysplasia
prior to referral for genetic testing.
3. Where one or both parents have Achondroplasia
the risk is 50 - 75%. NIPD is available to
pregnancies where there is a paternal mutation
only. The test cannot currently distinguish between
maternal DNA and fetal DNA in cases where there
is a maternal mutation.
Approval date: Sept 13
Copyright UKGTN © 2013
Submitting laboratory: London North East RGC GOSH
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INTENDED USE
(Please use the questions in Annex A to inform your answers)
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
Yes
No
Presymptomatic testing
(n/a for panel tests)
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.
14 have been cases tested (10 ACH and 4 TD). Outcome data to January 2013 was available for 7
cases and is concordant with the NIPD result in each case. Since January 2013, we have been able to
obtain 4 out of 7 outcomes for pregnancies ongoing in January 2013. Of the 5 cases reported to have
no mutation, three were confirmed to be normal at birth; we have been unable to obtain outcomes for
two overseas referrals. One case was reported to have the common ACH c.1138G>A mutation by NIPD
and this was confirmed when the baby presented with achondroplasia at birth. One case was reported
to have the TD c.1118A>G mutation; this pregnancy was terminated and no fetal material provided to
confirm our result. We continue to audit all pregnancy outcomes.
To ensure analytical sensitivity our protocol stipulates that fetal gestation must be a minimum of 9
weeks by ultrasound scan for a referral to be accepted and that samples of blood in EDTA must reach
the laboratory for plasma separation within 24-48 hours of sampling. If delay is anticipated blood taken
into cell stabilising (Streck) tubes is requested.
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 specificity for the test is high with the mutations tested for being fully penetrant.
The clinical sensitivity of this test is high:
For achondroplasia approximately 98% of cases have the c.1138G>A (p.Gly380Arg) mutation and a
further 1% are reported to have the c.1138G>C (p.Gly380Arg) mutation. Two other rare ACH mutations
(c.1123G>T (p.Gly375Cys) and c.1130T>G (p.Leu377Arg) are also included in the panel).
In severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) a single
mutation (c.1949A>T (p.Lys650Met)) has been reported in all cases to date.
For thanatophoric dysplasia, mutations in the FGFR3 gene have been identified in over 95% of
confirmed cases.
TD type I - Several recurrent mutations have been identified involving the gain of a cysteine residue,
including p.Arg248Cys (55% of cases), p.Tyr373Cys (24%), and p.Ser249Cys (6%). Rarer mutations
including p.Lys650Met, p.Gly370Cys and p.Ser371Cys have also been reported. Mutation of the stop
codon including p.*807Gly (c.2416T>G), p.*807Cys (c.2418A>T) and p.*807Arg (c.2416 T>A) accounts
Approval date: Sept 13
Copyright UKGTN © 2013
Submitting laboratory: London North East RGC GOSH
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for 10% of TD type I patients.
TD type 2 - A single mutation, c.1948A>G (p.Lys650Glu), has been reported in all cases to date.
Clinical sensitivity is lower for hypochondroplasia where two common mutations, c.1620C>A and
c.1620C>G, both of which result in the same protein change (p.Asn540Lys) account for ~70% of cases
Several other FGFR3 mutations that account for approximately 5% of cases would not be detected by
this test.
In Muenke syndrome, a single mutation, c.749C>G (p.Pro250Arg) has been reported in all cases to
date
The test is not applicable for women who themselves carry a panel mutation in FGFR3 as it cannot
distinguish a fetal mutation from the maternal background genotype.
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 positive predictive value is 100%.
The negative predictive value is high, but we cannot exclude the possibility of a rare FGFR3 (or other
gene) mutation that is not detected by this assay leading to a skeletal dysplasia phenotype.
Where outcomes are available results have been concordant; we are awaiting the outcomes for some
ongoing pregnancies.
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.
Not applicable.
CLINICAL UTILITY
28. How will the test change the management of the patient and/or alter clinical outcome?
Women with a known risk of germline mosaicism can have diagnostic information from 9 weeks in
pregnancy.
For cases identified by sonographic diagnosis, cffDNA testing is used to confirm FGFR3-related
skeletal dysplasia. The sonographic features can overlap with those seen in other skeletal dysplasias
which occasionally lead to misdiagnosis by ultrasound alone. cffDNA testing assists by giving a
definitive diagnosis, without a miscarriage risk, that will allow accurate prenatal counselling and avoid
inappropriate interventions. Furthermore, with increasing use of early ultrasound the sonographic
findings of severe, lethal skeletal dysplasias are increasingly being detected before 14 weeks.
Diagnosis at this stage of pregnancy allows women to undergo surgical termination of pregnancy but
this precludes definitive pathological postnatal diagnosis. The offer of NIPD to make a definitive
diagnosis of TD is welcomed by women in these circumstances as the main differential diagnosis at this
point in pregnancy are autosomal recessive conditions such as the short ribbed polydactyly syndromes.
If a definitive diagnosis of TD can be made women can then undergo surgical termination as further
structural examination is not required. Furthermore, in multiple pregnancies where one fetus is affected
but the other appears normal, availability of NIPT allows definitive diagnosis without jeopardising the
normal fetus, at the same time as allowing conservative management as TD is lethal.
The extension of the non-invasive test to include 95% of known TD mutations using a panel approach
improves the sensitivity and hence clinical utility of NIPD compared to the restriction assay.
References
1.
Khalil A, Pajkrt E, Chitty LS. Early prenatal diagnosis of skeletal anomalies. Prenat Diagn. 2011 Jan;31(1):115-24
Approval date: Sept 13
Copyright UKGTN © 2013
Submitting laboratory: London North East RGC GOSH
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2. Chitty LS, Griffin DR, Meaney C, Barrett A, Khalil A, Pajkrt E, Cole TJ. New aids for the non-invasive prenatal
diagnosis of Achondroplasia: dysmorphic features, charts of fetal size and molecular confirmation using cell-free fetal
DNA in maternal plasma. Ultrasound Obstet Gynecol 2011;37: 283-9
3. Chitty LS, Khalil A, Barrett AN, Pajkrt E, Griffin DR, Cole TJ. Safe, accurate prenatal diagnosis of thanatophoric
dysplasia using ultrasound and free fetal DNA. Prenat Diagn. 2012 in press
29. Benefits of the test for the patient & other family members
Please provide a summary of the overall benefits of this test.
Women seeking prenatal diagnosis can avoid the approximate 1% to 2% risk of miscarriage associated
with invasive testing.
Mutation analysis in early pregnancy gives definitive information to allow the couple to make decisions
about termination or to plan for the birth of an affected child. When prenatal testing is performed using
cffDNA women can avoid the risk of miscarriage associated with invasive testing and avoid putting an
unaffected child at risk. Women having cffDNA testing for achondroplasia have reported anecdotally the
benefits of testing using cffDNA in terms of reduced anxiety compared to invasive testing. When offered
later in pregnancy following identification of sonographic findings suggestive of achondroplasia, cffDNA
testing avoids the risk of precipitating preterm labour associated with invasive diagnostic testing, whilst
still allowing the opportunity of definitive diagnosis. At this stage in pregnancy this is helpful for parents
as they can prepare themselves for the birth of a child with this condition.
In a recent qualitative study, women interviewed about their experiences with cffDNA testing for fetal
sex determination had overwhelmingly positive attitudes to the test and valued the opportunity to have a
test with no risk of miscarriage.1
References
Lewis et al Non-invasive prenatal diagnosis for fetal sexing - what is the value for service users? European
Journal of Human Genetics. 2012
30. What will be the consequences for patients and family members if this test is not approved?
Pregnant women with a risk of recurrence due to germline mosaicism will have to wait until 11 weeks
gestation and then undergo an unnecessary invasive test. The invasive test itself may present a
greater risk to the pregnancy than recurrence of the condition.
For pregnancies with suggestive ultrasound findings where invasive testing is declined, uncertainty
about a diagnosis and the outcome of the pregnancy will remain until the birth of the child.
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.
For women with a known genetic risk, NIPD is the only method available at 9 weeks of pregnancy for
diagnosis of FGFR3-related skeletal dysplasia. CVS is available from 11 weeks. Thanatophoric
dysplasia can be diagnosed with ultrasound, however, the sonographic features of thanatophoric
dysplasia can overlap with other skeletal dysplasias which leads to misdiagnosis by ultrasound alone.
Achondroplasia can be diagnosed with ultrasound in the third trimester, however, the sonographic
features of achondroplasia can overlap with those seen in lethal skeletal dysplasias which occasionally
leads to misdiagnosis by ultrasound alone. Molecular testing is used to confirm the diagnosis and when
cffDNA testing is used a definitive diagnosis can be given without the miscarriage risk associated with
invasive testing.
32. Please describe any specific ethical, legal or social issues with this particular test.
There are no ethical, legal or social issues with this application of NIPD over and above those of
conventional prenatal diagnosis for FGFR3-related skeletal dysplasia. NIPD is only carried out if a valid
clinical indication is provided and referrals are only accepted from relevant clinicians. Earlier diagnosis
allows earlier termination of pregnancy.
Approval date: Sept 13
Copyright UKGTN © 2013
Submitting laboratory: London North East RGC GOSH
8
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.
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)
Type of test
Cost (£)
Molecular test
on invasive
sample
including
exclusion of
maternal cell
contamination
£360
Prenatal cell
culture and
karyotyping
£250
Sampling
and £326
counselling for
invasive
diagnosis
Total cost tests/procedures no longer required
£936
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
50
£936
46800
25000
21800
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
An unaffected woman aged 31 years was referred at a gestation of 11+6 weeks because her
previous pregnancy was shown to be affected by thanatophoric dysplasia. Invasive testing in the
former pregnancy had identified the FGFR3 mutation c.2421A>G (p.807Trpext*102).
Testing was therefore requested to rule out recurrence due to germline mosaicism.
At the time of referral cffDNA analysis by digital PCR or restriction enzyme digest was not available for
this mutation so an invasive procedure was performed to obtain CVS for analysis. No evidence of the
Approval date: Sept 13
Copyright UKGTN © 2013
Submitting laboratory: London North East RGC GOSH
9
mutation was detected by invasive testing.
As testing using cffDNA was not available, the only option for this patient to exclude the low risk of
recurrence due to germline mosaicism was to have an invasive test, putting her pregnancy at risk of
miscarriage.
As part of the validation of the FGFR3 NGS panel cffDNA testing was subsequently performed on a
maternal blood sample obtained at the same time as the CVS. No evidence of the mutation was
detected using the non-invasive test. If this analysis had been available the patient could have avoided
an invasive test and subsequent anxiety.
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
Type of test
Cost
Molecular test on
invasive sample
including
exclusion of
maternal cell
contamination
£360
Prenatal cell
culture and
karyotyping
£250
Sampling
counselling
invasive
diagnosis
and £326
for
£ 936
Case example two – post genetic test
An unaffected woman aged 39 years, pregnant with twins, was referred for testing due to ultrasound
indicating a diagnosis of thanatophoric dysplasia in one fetus.
Non invasive prenatal diagnosis was carried out on a maternal blood sample and the common
c.742C>T (p.Arg248Cys) mutation that accounts for 55% of TD1 cases was not detected by PCR
followed by restriction digest or by digital PCR.
Invasive testing was declined.
Subsequent analysis with the FGFR3 NGS skeletal dysplasia panel detected the c.1118A>G
(p.Tyr373Cys) mutation that has been reported in 24% of cases with thanatophoric dysplasia type 1.
Although a post mortem examination was declined, fetal X-rays were consistent with the diagnosis of
thanatophoric dysplasia.
The patient could then be offered accurate genetic counselling regarding recurrence risks.
Testing in future pregnancies is now available from 9 weeks gestation using non-invasive prenatal
diagnosis.
Approval date: Sept 13
Copyright UKGTN © 2013
Submitting laboratory: London North East RGC GOSH
10
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
dosier)
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
Type of test
Cost
Non-Invasive
Prenatal
Diagnosis using
FGFR3
NGS
Panel
£500
Results
£300
£800
37. Estimated savings between two case examples described £136
Approval date: Sept 13
Copyright UKGTN © 2013
Submitting laboratory: London North East RGC GOSH
11
UKGTN Testing Criteria
Test name: (for UKGTN administration to complete)
Approved name and symbol of disorder/condition(s):
OMIM number(s):
If a panel test please complete Testing Criteria appendix 1
Approved name and symbol of gene(s):
OMIM number(s):
If a panel test please complete Testing Criteria appendix 2
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 in Fetal Medicine
Consultant Clinical Geneticist
Minimum criteria required for testing to be appropriate as stated in the Gene Dossier:
Criteria
Tick if this patient
meets criteria
At risk pregnancy
Father has an FGFR3-related skeletal disorder OR
A previous pregnancy has been confirmed to have an FGFR3-related skeletal
dysplasia, thus there is a very small risk of recurrence due to germline mosaicism
Abnormal ultrasound findings compatible with a sonographic diagnosis of
FGFR3-related skeletal dysplasia
Achondroplasia (ACH) and other rarer forms of FGFR3 related skeletal
dysplasia including Muenke Syndrome, Hypochondroplasia and
Hypochondroplasia plus acanthosis nigricans:
Femoral length on or above the 3rd percentile (ie. within the normal range) at the
routine 18-20 week scan AND
Femur length and all long bones below the 3rd percentile after 25 weeks
gestation AND
Head circumference and abdominal circumference within or above the normal
range for gestation at diagnosis, fetal and maternal dopplers should be normal
Thanatophoric Dysplasia & severe achondroplasia with developmental delay
and acanthosis nigricans:
The following features must be present
1. All long bones below the 3rd percentile
2. Small chest with short ribs
3. Additional features:
Polyhydramnios, Bowed femora, Relative macrocephaly, Cloverleaf skull,
Short fingers
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 13
Submitting laboratory: London North East RGC GOSH
Copyright UKGTN © 2013
12
Approval date: Sept 13
RGC GOSH
Copyright UKGTN © 2013
Submitting laboratory: London North East
13
Approval date: Sept 13
RGC GOSH
Copyright UKGTN © 2013
Submitting laboratory: London North East
14
Testing Criteria appendix 1
Conditions in panel test
OMIM standard name of condition and symbol
Thanatophoric dysplasia Type I; TD1
Thanatophoric dysplasia Type II; TD2
Achondroplasia; ACH
Muenke Syndrome; MNKES
Hypochondroplasia; HCH
Hypochondroplasia plus acanthosis nigricans
Severe achondroplasia with developmental delay and acanthosis nigricans
(SADDAN)
OMIM number
187600
187601
100800
602849
146000
187600
Testing Criteria appendix 2
Genes in panel test
HGNC standard name and symbol of the gene
HGNC
number
3690
Fibroblast Growth Factor Receptor 3 (FGFR3)
Approval date: Sept 13
RGC GOSH
Copyright UKGTN © 2013
OMIM number
134934
Submitting laboratory: London North East
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