Download Distal Arthrogryposis - 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: Bristol RGC
1. Disorder/condition – approved name and
symbol as published on the OMIM
database (alternative names will be listed on the
Approved: Sept 2013
Arthrogryposis, Distal, Type 1A; DA1A
Arthrogryposis, Distal, Type 2B; DA2B (Sheldon-Hall
syndrome)
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
108120 Arthrogryposis, Distal, Type 1A; DA1A
601680 Arthrogryposis, Distal, Type 2B; DA2B
Distal Arthrogryposis (DA) is a group of disorders
characterised by congenital contractures in the distal
limbs without an obvious neurogenic or myopathic
cause.
Ten different clinical forms (DA1 to DA10) have been
described, with DA1 and DA2B as the most common
forms and some other very rare forms.
Features shared amongst all distal arthrogryposes
include consistent patterns of hand and foot
involvement, limited involvement of proximal joints,
and variable expressivity within families.
Patients usually have a normal lifespan, some
become completely independent, others continue to
require assistance. Limitations are mainly regarding
pain and muscle fatigue, but in some cases also have
quite severe limitations of joint mobility. Many patients
are required to undergo repeated surgical intervention.
DA1 is characterised by camptodactyly and talipes,
but the shoulders and hips may sometimes be
affected. Hypoplasia is common. The degree to which
the joints are affected is highly variable.
DA2B (Sheldon-Hall Syndrome) is a relatively mild
form of arthrogryposis which is characterised by small
mouth, facial contractures, scoliosis, mainly distal
contractures and short stature.
Mutations in genes encoding sarcomeric muscle
proteins are found in several DA syndromes.
Mutations in TPM2 and MYBPC1 (*160794) have
been described in patients with DA1.
Mutations in TPM2, TNNI2 (*191043), TNNT3
(*600692) and MYH3 (*160720) cause DA2B.
Autosomal Dominant and de novo
tropomyosin 2 (beta); TPM2
names will be listed on the UKGTN website)
6a. OMIM number for gene(s)
190990
6b HGNC number for gene(s)
HGNC:12011
7a. Gene – description(s)
TPM2, chromosome location 9p13.3.
The TPM2 gene encodes beta-tropomyosin, an
isoform of tropomyosin that is mainly expressed in
slow, type 1 muscle fibers.
Approval Date: Sept 2013
Submitting Laboratory: Bristol RGC
Copyright UKGTN © 2013
There are two isoforms: The skeletal muscle isoform
and the fibroblast isoform in which alternative splicing
of exons 6 & 9 occur.
Mutations have been described in the skeletal muscle
isoform – cDNA 1189bp, amino acids 284, 9 exons.
Tropomyosin is a member of the actin filament binding
protein family (in muscle and non-muscle cells) and
part of a multimeric complex of the sarcomere (along
with actin, troponins C, I, T and myosin) (Tajsharghi H
et al 2008 Arch Neurol 65(8);1083-1090); mutations
appear to affect myofibre contractility (Bamshad M et
al 2009 J Bone Joint Surg Am. 91 Suppl 4:40-6),
Mutations in the TPM2 gene also cause Nemaline
Myopathy (#609285), Cap Disease (#609285), and as
yet unspecified congenital myopathy.
Tajshargi H et al (2012) Neuromsucular Disorders
22:923-933.
9 amplicons, including coverage of alternative exons 6
& 9.
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
GenU band E
8. Mutational spectrum for which you test
including details of known common
mutations
Sanger sequence analysis of the entire coding regions
of genes, splice sites and branch points for point
mutations and small insertions and deletions.
Human Gene Mutation Database (HGMD) indicates
that 10 (14 in HGMD professional) TPM2 mutations
have been detected so far including substitution and
small insertion/deletion mutations. Only 1 mutation on
this database is associated with DA (the others are
associated with nemaline myopathy and muscle
weakness and distal limb deformity).
100% reported TPM2 mutations are detectable by
sequencing.
The Leiden Muscular Dystrophy database
(www.LOVD.nl/TPM2) lists 32 unique TPM2 variants
to date; 6 mutations are associated with DA (3
missense mutations and 3 possibly affecting splicing)
which would be detected by sequencing.
High Throughput (HT) Automated sequence analysis.
Gene screening by bidirectional automated HT
sequence analysis (Beckman NX/ABI3730), the
standard platform used for gene screening at BGL and
analysis of the results with Mutation Surveyor
software.
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
Section not applicable
n/a
n/a
Submitting Laboratory: Bristol RGC
Copyright UKGTN © 2013
iv) If NGS is used, does the lab adhere to
the Practice Guidelines for NGS?
n/a
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.
Assay to be provided by Bristol Genetics Laboratory
11. Validation process
Please explain how this test has been
validated for use in your laboratory or submit
your internal validation documentation
HT automated sequence analysis:
This method is routinely used to screen for mutations
at BGL and had been validated for many services.
Beckman NX robotics /ABI 3730 capillary
electrophoresis and mutation surveyor software
analysis are routinely used in the laboratory. Positive
and negative control samples are included.
Primers (SNP checked) have been designed to cover
the coding regions and intron-exon boundaries.
BGL also participates in external quality assurance
EMQN sequencing QA schemes (since the pilot
scheme was introduced in 2002).
The assay has been validated on known normal
controls stored in the laboratory.
We do not have access to DNA from patients tested in
research laboratories to use as positive controls for
validation purposes.
12a. Are you providing this test already?
No
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.
n/a
12c. Number of reports mutation positive
n/a
12d. Number of reports mutation negative
n/a
13. For how long have you been providing
this service?
n/a
14a. Is there specialised local
clinical/research expertise for this
disorder?
14b. If yes, please provide details
Yes
15. Are you testing for other
genes/disorders/conditions closely allied
to this one? Please give details
Dr Sarah Smithson, Consultant in Clinical Genetics, St
Michael’s Hospital, Bristol
We currently offer a service for TAR Syndrome at
BGL. TAR Syndrome (Thrombocytopenia with Absent
radius) is a rare genetic disorder that is characterized
by the absence of the radius bone in the forearm, and
a dramatically reduced platelet count (#274000).
Dr Sarah Smithson has a special interest in skeletal
and craniofacial disorders.
Dr Ruth Newbury-Ecob, Clinical Genetics, UHB has a
Approval Date: Sept 2013
Submitting Laboratory: Bristol RGC
Copyright UKGTN © 2013
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?
specialist interest in limb abnormalities, such as HoltOram Syndrome (#142900) which is characterised by
heart and upper limb defects.
It is difficult to assess the demand for the service as
this has not been available to clinicians previously. We
anticipate we may receive up to 10 referrals in the first
year but this may increase with awareness of the
service.
~10 in first year
Not yet known, estimate of 30 (2 parents and one sib
for each case above)
The capacity in BGL is available to meet demand for
UK.
n/a
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.
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: Bristol RGC
Copyright UKGTN © 2013
EPIDEMIOLOGY
The prevalence of arthrogryposis is approx. 1/3000
[Hall et al 1982). The most common forms are DA1
and DA2B.
19a. Estimated prevalence of condition in
the general UK population
Epidemiological data for the distal arthrogryposis (DA)
syndromes are not available, but anecdotal data
suggest that DA2B is the most common of the DAs
and the most frequent cause of heritable
arthrogryposis. The prevalence of DA appears to be
similar across different populations although most of
the individuals reported to date are of European
ancestry. There is no known sex bias (Toydemir &
Bamshad 2009)
In a large study of over 350 patients with
arthrogryposis, 44 (12.6%) patients with DA were
identified. In another review, 35% of 155 patients with
arthrogryposis were diagnosed with DA. In an
epidemiological survey from western Sweden, 5 (7%)
patients with DA syndromes were identified in a total
of 68 patients with multiple congenital contractures.
References:
Bamshad, M., Van Heest, A. E., Pleasure, D. Arthrogryposis: a
review and update. J. Bone Joint Surg. Am. 91: 40-46, 2009
Bamshad, M., Jorde, L. B., Carey, J. C. A revised and extended
classification of the distal arthrogryposes. Am. J. Med. Genet. 65:
277-281, 1996
Sarwark JF, MacEwen GD, Scott CI, Jr. Amyoplasia (a common
form of arthrogryposis).
The Journal of bone and joint surgery. 1990 Mar;72(3):465-9.
Darin N, Kimber E, Kroksmark AK, Tulinius M. Multiple congenital
contractures:
birth prevalence, etiology, and outcome. J Pediatr. 2002
Jan;140(1):61-7.
Hall, J.G. (1985) Genetic aspects of arthrogryposis. Clin. Orthop.
Relat.
Res., 194, 44–53.
Hall, J G et al (1982) The distal arthrogryposes: Delineation of
new entities – review and nosologic discussion. Am J Med Genet:
11 185-239.
Toydemir & Bamshad (2009) Sheldon-Hall Syndrome – review.
Orphanet Journal of Rare Diseases 4:11.
19b. Estimated incidence of condition in
the general UK population
Please identify the information on which this is
based
20. Estimated gene frequency (Carrier
frequency or allele frequency)
Please identify the information on which this is
based
Approval Date: Sept 2013
Limited data for UK population available. Incidence of
DA1 in US population is ~ 1:10,000.
Bamshad M et al (1996) Am J Med Genet. 65:27781.Hall JG (1985) Clin Orthop Relat Res. ;194:
44-53.
We have not been able to establish the carrier
frequency from the literature.
Please note that some cases have been described
with de novo mutations. Tajsharghi et al (2007)
Neurology 68: 772-775
Submitting Laboratory: Bristol RGC
Copyright UKGTN © 2013
21. Estimated penetrance
Please identify the information on which this is
based
22. Estimated prevalence of condition in
the population of people that meet the
Testing Criteria.
Penetrance is highly variable in this condition so a
mildly affected parent may have a severely affected
child. Genetic testing will be very helpful in the
diagnosis of mildly affected patients and family
members.
Target Population:
1. Patients with Distal Arthrogryposis type 2B
2. Patients with Distal Arthrogryposis type 1.
It is not known what proportion of DA2B cases have
mutations in TPM2. Published mutations include the
p.Arg133Trp mutation found in a mother and daughter
with DA2B.
Tajsharghi, H., Kimber, E., Holmgren, D., Tulinius, M.,
Oldfors, A. Distal arthrogryposis and muscle
weakness associated with a beta-tropomyosin
mutation. Neurology 68: 772-775, 2007.
Currently only one mutation in TPM2 has been
described in a patient with with DA1.
Sung, S. S., Brassington, A.-M. E., Grannatt, K.,
Rutherford, A., Whitby, F. G., Krakowiak, P. A., Jorde,
L. B., Carey, J. C., Bamshad, M. Mutations in genes
encoding fast-twitch contractile proteins cause distal
arthrogryposis syndromes. Am. J. Hum. Genet. 72:
681-690, 2003.
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 - possible influence on
surgical management
No
Prognosis & management
Presymptomatic testing
Yes
(n/a for panel tests)
No
Yes - to identify
unaffected/minimally affected
gene carrier
No
Carrier testing for family members (n/a for panel tests)
Yes
No
Prenatal testing
Yes - Possible
No
Approval Date: Sept 2013
(n/a for panel tests)
Submitting Laboratory: Bristol RGC
Copyright UKGTN © 2013
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.
High Throughput Semi Automated Sequence analysis.
Sensitivity 99-100%.
To the best of our knowledge, no variant has been missed using a bi-directional sequencing approach.
SCOBEC validation of unidirectional sequencing indicates a sensitivity of 99%.
The sensitivity for detecting mutations in TPM2 will be 99% based on the mutations reported so far.
Large deletions/duplications have not been reported in the TPM2 gene.
Specificity > 99%
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
Currently only one mutation in TPM2 has been described in a patient with DA1.
References: Sung, S. S., Brassington, A.-M. E., Grannatt, K., Rutherford, A., Whitby, F. G., Krakowiak,
P. A., Jorde, L. B., Carey, J. C., Bamshad, M. Mutations in genes encoding fast-twitch contractile
proteins cause distal arthrogryposis syndromes. Am. J. Hum. Genet. 72: 681-690, 2003.
DA1 is also caused by mutations in the MYBPC1 gene (*160794) which we don’t currently test (no
UKGTN service).
Collectively, mutations in the MYH3 (*160720), TNNI2 (*191043), and TNNT3 (*600692) genes account
for about half of all studied cases of DA2B. It is not known what proportion of DA2B cases have
mutations in TPM2. Published mutations include the p.Arg133Trp mutation found in a mother and
daughter with DA2B.
References: Toydemir, R. M., Rutherford, A., Whitby, F. G., Jorde, L. B., Carey, J. C., Bamshad, M. J.
Mutations in embryonic myosin heavy chain (MYH3) cause Freeman-Sheldon syndrome and SheldonHall syndrome. Nature Genet. 38: 561-565, 2006.
Tajsharghi, H., Kimber, E., Holmgren, D., Tulinius, M., Oldfors, A. Distal arthrogryposis and muscle
weakness associated with a beta-tropomyosin mutation. Neurology 68: 772-775, 2007.
Clinical specificity :
Presumed over 95%, depending on the basis of interpretation of sequence variants as ‘consensus’
mutations, or as innocuous polymorphisms.
For testing relatives: Clinical sensitivity and specificity: will both be 100% when the mutation is definitely
pathogenic.
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).
Clinical validity: In an index case, finding one pathogenic mutation confirms the diagnosis in the
majority of cases.
We estimate that for index casesPositive predictive value (PPV) = 100% for consensus mutations
Negative predictive value (NPV) = greater uncertainty but likely to approach 100%
Approval Date: Sept 2013
Submitting Laboratory: Bristol RGC
Copyright UKGTN © 2013
If looking at TPM2 alone the NPV is 100% but according to recent data by Beck et al (2013) Am J Med
Genet A 161(3):550-555, TPM2 mutations account for approx. 9% of cases of DA1 and DA2B overall.
The paper reports that the genetic basis of DA1/DA2B can be explained in <50% of cases, although in
this study the percentage of patients positive for a mutation out of the genes tested was 37%. Note:
Cohort size: 153; genes tested TPM2, TNNT3, TNN12 and MYH3.
However, for testing family members, PPV and NPV are both effectively 100% for carrier status using
consensus mutations.
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.
Currently we are only developing a test for the TPM2 gene.
CLINICAL UTILITY
28. How will the test change the management of the patient and/or alter clinical outcome?
The DA group is clinically heterogeneous (with extensive phenotypic variability between and within
families) and it can be very difficult to decipher the different types and importantly distinguish them from
primary muscle and neurological disorders which can also present with congenital contractures. The
prognosis in DA type 1 is usually good with appropriate physiotherapy and surgical intervention when
necessary and furthermore patients have normal development. The prognosis in some of the
neurological conditions may be very different so early diagnosis is important to advise parents correctly
and initiate the right treatment.
If the molecular genetic basis can be identified, it can be clearly established whether the parents carry
the mutation and accurate genetic counselling provided. It is important to distinguish between the very
low risk (if a de novo mutation) or high 50% risk (if present in a parent).
In rare instances parents may request prenatal diagnosis if they have had a very severely affected
infant before. Some patients may have breathing difficulties if there is analysis of the jaw and
sometimes this requires a tracheostomy.
29. Benefits of the test for the patient & other family members
Please provide a summary of the overall benefits of this test.
Firstly testing will enable a precise diagnosis in this difficult group with clinical overlap with a wide
variety of neurological conditions presenting with contractures. This will allow clinicians to decide on
appropriate management and avoid invasive investigations such as muscle biopsy in some patients.
Molecular investigation is important in order to further define and understand this disorder and provide
accurate genetic counselling.
In some families with a more severe phenotype the option for early prenatal diagnosis will be possible.
30. What will be the consequences for patients and family members if this test is not approved?
Uncertain diagnosis, they may be misinformed about the outcome for their child, they may have another
affected child without being aware of the risk.
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.
The diagnosis is clinical supported by X ray investigations and the absence of any biochemical or
muscle disorder. Very rare cases of congenital contractures (which mimic DA) may be caused by
maternal myasthenia gravis where the mother produces antibodies to fetal acetylcholine receptors at
the neuromuscular junction, then the antibodies may be measured in maternal serum.
The great advantage of the molecular test is that numerous other invasive tests such as nerve
conduction studies and muscle biopsy may be avoided if the diagnosis can be established early.
Approval Date: Sept 2013
Submitting Laboratory: Bristol RGC
Copyright UKGTN © 2013
32. Please describe any specific ethical, legal or social issues with this particular test.
There are no specific issues with this test. Parents would require counselling to understand the highly
variable gene penetrance prior to testing. Prenatal diagnosis may only be requested in a few families
for example if a child had been severely affected.
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.
Total cost tests/procedures no longer required
Type of test
Cost (£)
Costs and type of imaging procedures
Brain MRI scan
Spine MRI scan
£230
Costs and types of laboratory pathology tests
(other than molecular/cyto genetic test proposed in this Urine MPS
gene dossier)
Carnitines
26.16
£84.44
CPK
£0.93
Lactate
£8.33
Ammonia
£16.61
White cell
enzymes
£65.10
Plasma amino
acids and urine
organic acids
Costs and types of physiological tests (e.g. ECG)
Nerve
conduction
studes
EMG
Cost and types of other investigations/procedures (e.g. Muscle biopsy
biopsy)
£58.81
£180
£180
£538
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
Approval Date: Sept 2013
(a) initially up to 10
(b) £1158
10 x £1158.38= £11583
10 x 522 = £5220 cost of genetic testing for index
case
11583-5220=£6363.8
Submitting Laboratory: Bristol 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
A young adult man with DA type 1 had been born with distal contractures of his hand and feet. These
were treated with staged surgical procedures over the years and he was able to achieve good hand
function; he had completely normal intellect. He had been incorrectly advised that he did not have a
genetic condition and did not have access to genetic diagnosis or counselling prior to having his first
child who was also affected with DA1, although more severely so. This came as a shock to him and he
was initially very upset as he had not understood the risk to his children. The diagnosis of DA 1 was
made on clinical and radiological grounds, but in this case access to genetic testing would have been
helpful to delineate the type of arthrogryposis and confirm the genetic risk.
Genetic testing would also be very helpful to those children who are the first to be affected in their
families where the differential diagnosis in infancy can be quite broad.
Case example two – post genetic test
The service is not yet available hence we are not able to provide this
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)
Type of test
MRI scan
Metabolic
Nerve conduction
and EMG
Muscle Biopsy
Genetics and nongenetics
Total cost pre genetic test
Cost
£230
£260.38
£360 (£180 each)
£538
£2000
£3388.38
Case example two – post genetic test
The service is not yet available hence we are not able to provide this as a case study
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
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
Type of test
Not required
Not required
Cost
-
Not required
Not required
As above
£522
2000
£2522
37. Estimated savings between two case examples described £866.38
Approval Date: Sept 2013
Submitting Laboratory: Bristol RGC
Copyright UKGTN © 2013
UKGTN Testing Criteria
Test name:
Distal Arthrogryposis
Approved name and symbol of disorder/condition(s):
Arthrogryposis, Distal, Type 1A; DA1A
Arthrogryposis, Distal, Type 2B; DA2B
Approved name and symbol of gene(s):
tropomyosin 2; TPM2
OMIM number(s):
108120
601680
OMIM number(s):
190990
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 Geneticist
Minimum criteria required for testing to be appropriate as stated in the Gene Dossier:
Criteria
Tick if this patient
meets criteria
Distal arthrogryposes characterised by congenital
contractures of hand and foot and limited involvement of proximal joints
AND
Absence of primary neurological and/or muscle disease AND
Affected with two or more of the following:
Upper limb:
• camptodactyly or pseudocamptodactyly
• hypoplastic and/or absent flexion creases, overriding fingers, and
ulnar deviation at the wrist.
Lower limb:
talipes equinovarus, calcaneovalgus deformities, vertical talus, and/or
metatarsus varus
(Distinct facial features: triangular face, prominent nasolabial folds,
downslanting palpebral fissures, small mouth).
OR
At least one major diagnostic criterion where first-degree family member
(i.e., a parent or a sibling) meets the above diagnostic
criteria
At risk family members where familial mutation is known.
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: Bristol RGC
Copyright UKGTN © 2013