Download Proposal form for the evaluation of a genetic test for NHS Service

Proposal form for the evaluation of a genetic test for NHS Service
Gene Dossier/Additional Provider
TEST – DISEASE/CONDITION – POPULATION TRIAD
Submitting laboratory: Bristol RGC
1. Disease/condition – approved
name and symbol as published on
the OMIM database (alternative names will
Approved: Sept ember 2012
Charcot-Marie-Tooth Hereditary Neuropathy
Hereditary Motor Neuropathy
Hereditary Sensory Autonomic Neuropathy
be listed on the UKGTN website)
2. OMIM number for
disease/condition
See Table 1 at the end of this document
3. Disease/condition – please
provide a brief description of the
characteristics of the
disease/condition and prognosis for
affected individuals. Please provide
this information in laymen’s terms.
Charcot-Marie-Tooth (CMT) or Hereditary Motor and Sensory
Neuropathy refers to a group of disorders characterised by
weakness and wasting of the muscles below the knees and
often those of the hands. Many affected people also have
loss of feeling in the hands and feet. The underlying cause is
that the peripheral nerves (which connect the spinal cord to
the muscles, joints and skin, carrying messages in both
directions) do not function normally, due to genetic mutations.
There are more than 50 genes associated with the different
types of inherited neuropathy. Determining the exact kind of
CMT someone has is important. It distinguishes it from other
non-genetic causes of neuropathy which require different
treatment, this is particularly important for people who do not
have affected relatives. Establishing the genetic diagnosis
assists in the prognosis and future management of the patient
and their family.
Charcot-Marie-Tooth (CMT) Hereditary Neuropathy refers to
a group of disorders characterized by a chronic motor and
sensory polyneuropathy. The disease results from
involvement of peripheral nerves that can affect the motor
system and/or the sensory system. The patient typically has
distal muscle weakness and atrophy often associated with
mild to moderate sensory loss, depressed tendon reflexes,
and high-arched feet.
Patients have progressive difficulties with walking and
balance due to the ‘contracted’ shape of their feet, the
weakness in the muscles of the lower leg and at the ankle,
and a loss of sensation or position sense of the feet. Similarly
in the hands patients develop weakness, numbness and
contractures of the fingers making many tasks which require
fine finger control become impossible. There can be
associated hearing loss, and in some forms patients develop
serious breathing problems from involvement of the nerve to
the diaphragm.
Due to heterogeneity of this group of disorders, a total of 66
different variants of phenotype have been considered; these
are linked with 54 different genes. The main phenotypic
groups are described below.
CMT type 1 is a demyelinating peripheral neuropathy
characterized by distal muscle weakness and atrophy,
sensory loss, and slow nerve conduction velocity (typically 530 m/sec; normal: >40-45 m/sec). There are 6 subtypes
Approval Date: Sept 2012
Submitting Laboratory: Bristol RGC
Copyright UKGTN © 2012
4. Disease/condition – mode of
inheritance
5. Gene – approved name(s) and
symbol as published on HUGO
database (alternative names will be listed on
linked with respective genes. See Table 1.
CMT type 2 is an axonal (non-demyelinating) peripheral
neuropathy characterized by distal muscle weakness and
atrophy. Nerve conduction velocities are usually within the
normal range; however, occasionally they fall in the lownormal or mildly abnormal range (35-48 m/sec). Peripheral
nerves are not enlarged or hypertrophic. There are 16
subtypes linked with known genes. See Table 1.
Intermediate CMT (DI-CMT) is characterized by a relatively
typical CMT phenotype with clinical and pathologic evidence
of both abnormal myelin and axonopathy. Nerve conduction
velocities (NCVs) overlap those observed in CMT1 and
CMT2. Motor NCVs usually range between 25 and 50 m/sec.
There are 4 characterised subtypes linked with known genes.
See Table 1.
CMT type 4 is a group of progressive motor and sensory
axonal and demyelinating neuropathies. It is distinguished
from other forms of CMT by the autosomal recessive
inheritance. Patients have the typical CMT phenotype of
distal muscle weakness and atrophy associated with sensory
loss and, frequently, pes cavus foot deformity. There are 9
subtypes linked with known genes. See Table 1.
CMT X-linked is characterized by a moderate to severe motor
and sensory neuropathy in affected males and usually mild to
no symptoms in carrier females. Sensorineural deafness and
central nervous system symptoms also occur in some
families. There are 2 subtypes linked with known genes. See
Table 1.
Hereditary motor neuropathies (HMN) are associated with
distal weakness without sensory loss. There are 9 HMNrelated subtypes linked with mutations in known genes. See
Table 1.
Hereditary sensory neuropathies (HSN). Several autosomal
dominant axonal neuropathies have primarily sensory
symptoms and are classified as hereditary sensory
neuropathies. Distal weakness may also occur. There are
also some recessively inherited subtypes. There is a total of 9
subtypes linked with known genes, see Table 1.
Rare clinical phenotypes where neuropathy is a main feature
but do not fit in any of the above phenotypic groups, either
because there are lot of extra clinical features, or overlap of
phenotypes. There are 10 different phenotypes, see Table 1.
Autosomal Dominant (AD)
Autosomal Recessive (AR)
X- Linked (XL)
All three modes of inheritance are present, please see Table
1, next to each phenotype the mode of inheritance is
indicated.
See Table 2.
A total of 54 genes included in this approach.
the UKGTN website)
6. OMIM number for gene(s)
Approval Date: Sept 2012
See Table 2.
Submitting Laboratory: Bristol RGC
Copyright UKGTN © 2012
7. Gene – description(s)
7b. Number of amplicons to provide
this test
7c. MolU/Cyto band that this test is
assigned to
8. Mutational spectrum for which
you test including details of known
common mutations
9. Technical method(s)
10. Validation process
Please explain how this test has been
validated for use in your laboratory
Approval Date: Sept 2012
See Table 2. A total of 54 genes are included in this assay.
More genes may be added in the future to the service, as
evidence regarding their association with the clinical
phenotype becomes available.
See Table 2. In brief there are 955 regions of interest (ROI:
coding exons, 5’ and 3’ UTRs).
Band G is the ‘highest’ band and designed to represent > 40
amplicons; this approach covers 955 regions of interest and
the equivalent would be > 1000 amplicons.
Analysis of the coding regions for point mutations and small
insertion/deletions.
Targeted selection of the genes using SureSelect Capture
method (Agilent). Next Generation Sequencing (NGS)
analysis using Illumina MiSeq platform.
Sanger Sequencing for confirmation of the positive results.
Approximately 70% of the CMT1 cases are caused by
duplication of the PMP22 gene. This is detected by MLPA,
with an established protocol in the laboratory. This will remain
the first line of test for the typical demyelinating cases, as
currently there is not sufficient evidence that NGS technology
can robustly detect copy number variation.
Sanger sequencing of genes is the current method of testing
for mutations, established for more than 30 genes.
Two pilot projects in Bristol Genetics Laboratory (BGL) are
undergoing the final steps of validation, one for Familial
Hypercholesterolemia (FH) and one for Inherited Peripheral
Neuropathies (IPN). Two different capture methods (Agilent
Sure Select for IPN and Haloplex for FH) have been used,
and bioinformatics pipeline has been established for quality
checking and data analysis. Both projects have run on to the
MiSeq, in BGL, while the IPN library has also run onto
Illumina GAII in Bristol University for comparison of the data
produced.
The IPN cohort consisted of 10 patients, previously tested for
the genes available in service and a total of 22 SNPs have
been identified in the previous investigations using Sanger
sequencing; these served as controls to establish the
parameters and thresholds of the assay. These were
missense, silent and intronic variants and they were all
detected correctly with the NGS assay.
A Bioinformatics pipeline was established to check the quality
of the library and analyse the results. Data QC revealed high
quality data, with low duplication rate, high reads mapping to
the genome and good coverage for both capture methods
(95% of targets > x30 reads).
A total of 770 unique variants were detected across the 10
IPN patients (8 patients with unknown mutations and 2 with
dosage abnormalities). Filtering these data against
dbSNP132 and 1000 Genomes data (applying MAF) and
applying the final QC left 27 unique novel variants (missense,
nonsense, silent, frameshift, small deletions, splicing). These
were further investigated using in silico tools (Alamut) and 9
were scored as potentially pathogenic, all of which
Submitting Laboratory: Bristol RGC
Copyright UKGTN © 2012
subsequently were confirmed by Sanger sequencing
indicating no false positive variant calling.
Through this validation 7/8 previously undiagnosed patients
have a potential genetic diagnosis while no candidate
pathogenic variant was found in one patient. All SNPs
previously detected by Sanger sequencing were correctly
identified giving a technical sensitivity of 100% with no
evidence for false positive variant calling as all potentially
pathogenic variants identified were confirmed by Sanger
sequencing.
The two patients with PMP22 dosage abnormalities tested
were successfully confirmed as duplication and deletion of
PMP22.
We are now at the stage of communicating the results to the
clinical teams to initiate family segregation studies to
determine whether the candidate pathogenic variants cosegregate with the disease or are de novo; this is the
common practice in the laboratory when a novel variant is
detected.
A larger cohort could not be included in this validation study
due to assay cost / size of the target region. On completion of
the segregation studies, if it is considered that a second pilot
study is required it will be undertaken at that time.
No
In part, see below.
11a. Are you providing this test
already?
11b. If yes, how many reports have
you produced?
We do not provide testing using next generation sequencing;
however the Bristol Genetics Laboratory is a specialist centre
for testing for inherited peripheral neuropathies. We currently
offer MLPA analysis for PMP22 dosage abnormalities, and
sequential screen for the following 14 genes listed in the table
below; Gene Dossiers have been approved for these genes
in the past.
Gene
Gene
MIM
Gene Dossier
PMP22
601097
N/A
MPZ
159440
N/A
GJB1
304040
N/A
SPTLC1
605712
N/A
EGR2
129010
2007
NEFL
162280
2007
PRX
605725
2007
LITAF
603795
2009
MFN2
608507
2010
HSPB1
602195
2010
HSPB8
608014
2010
BSCL2
606158
2010
RAB7
602298
2011
DYNC1H1*
600112
N/A*
* This has been implemented in service recently, following a
successful collaboration project with the Exeter Genetics
laboratory and University, where exome sequencing of a local
Approval Date: Sept 2012
Submitting Laboratory: Bristol RGC
Copyright UKGTN © 2012
family revealed a ‘new’ gene as the cause of neuropathy for
this family.
(Exome sequencing identifies a DYNC1H1 mutation in a large
pedigree with dominant Charcot- Marie -Tooth disease.
Weedon MN, Caswell R, Hastings R, Xie W, Paszkiewicz K,
Antoniadi T, Williams M, Newbury-Ecob R, Ellard S. American
Journal of Human Genetics, 89:1-5, 2011)
Data from a 3 year audit suggest the following pick up rates:
11c. Number of reports mutation
positive
Gene
tested
mutation
%
negative
PMP22
(sequencing
only)
MPZ
191
13
6.8%
178
181
7
3.9%
174
LITAF*
7
0
0
7
EGR2
30
1
3.3%
29
NEFL
45
2
4.4%
43
70
MFN2
81
11
13.6%
RAB7*
3
0
0
3
PRX
18
0
0
18
133
GJB1
159
26
16.4%
HSPB1*
11
2
18.2%
9
HSPB8*
11
0
0
11
BSCL2*
11
0
0
11
SPTLC1
21
2
9.50%
19
Genes marked with * were not in service during the audit
period, their pick up rate is based on data from April to
October 2011 (7 months).
11d. Number of reports mutation
negative
See above.
12. For how long have you been
providing this service?
BGL has been working since 1998 providing testing for
peripheral neuropathies.
13a. Is there specialised local
clinical/research expertise for this
disease?
13b. If yes, please provide details
Yes
14. Are you testing for other
genes/diseases/conditions closely
allied to this one? Please give details
Approval Date: Sept 2012
BGL is one of the two laboratories working in a collaborative
way to provide specialist UKGTN peripheral neuropathy
services; is a member of the European CMT Consortium and
has participated in national and European meetings.
Dr Peter Lunt is the Consultant Clinical Geneticist with special
interest in neurogenetics, and works together with a
dedicated Paediatric and Adult Neurologist (Dr Anirban
Majumdar and Dr Andria Merrison respectively) in a
dedicated Neuromuscular Disease service.
BGL is a specialist UKGTN laboratory and the SCOBEC
centre for peripheral neuropathies. UKGTN service provision
for:
Submitting Laboratory: Bristol RGC
Copyright UKGTN © 2012
Your current activity
If applicable - How many tests do you
currently provide annually in your
laboratory?
Gene
Gene MIM
PMP22
601097
MPZ
159440
GJB1
304040
SPTLC1
605712
EGR2
129010
NEFL
162280
PRX
605725
LITAF
603795
MFN2
608507
HSPB1
602195
HSPB8
608014
BSCL2
606158
RAB7
602298
DYNC1H1
600112
The NGS approach is a multigene panel with the aim of
providing a comprehensive rapid service for this group of
conditions.
A. Based on last year’s data (audit period 2010-2011), for
point mutations in the 8 genes we provided service for
(PMP22, MPZ, GJB1, MFN2, NEFL, EGR2, PRX, SPTLC1),
we have performed 257 sequencing screens.
B. For increased accuracy, in order to have a better
representation of all the genes we currently provide service
for, data for a 7 month period (April to October 2011), show
that for all the genes we have provided a total of 240 tests:
196 tests for the genes mentioned above and 44 tests for the
remaining genes (LITAF, RAB7, HSPB1, HSPB8, BSCL2,
DYNC1H1).
15a. Index cases
A. 257 tests were performed to 153 patients (for one or more
genes: PMP22, MPZ, GJB1, SPTLC1, EGR2, NEFL, PRX,
MFN2); this is this 2010-2011 data and some of these
patients have been tested for more genes before and after
this period.
B. 44 tests were performed to 18 patients for LITAF, RAB7,
HSPB1, HSPB8, BSCL2, DYNC1H1 in the period April to
October 2011. ie. est. 75-80 tests annually
15b. Family members where
mutation is known
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?
16a. Index cases
16b. Family members where
mutation is known
31
Approval Date: Sept 2012
The capacity in BGL is available to meet demand for UK and
international referrals.
Estimate:
Minimum: 5 samples per week = >300 samples per year
Maximum: 20 samples /week=>1000 samples a year
Up to 1000 / yr
Up to 2x positive index cases ( 2 x 500 = 1000 /yr)
Submitting Laboratory: Bristol RGC
Copyright UKGTN © 2012
Based on experience how many
tests will be required nationally (UK
wide) per annum?
Please identify the information on
which this is based
Based on previous year’s BGL data, we estimate at least 200
patients will be tested; this is likely to increase as this
comprehensive approach increases the chance of a genetic
diagnosis in all cases with unclassified CMT.
This does not include patients that have already been tested
and have not got a genetic diagnosis; clinicians will re-refer
some of these patients for this new analysis.
17a. Index cases
17b. Family members where
mutation is known
18. National activity (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.
200-250 by NGS
80-100 by Sanger Sequencing
There is no other UK laboratory currently listed by UKGTN
providing this type of panel testing. We are able to provide
for all UK cases.
ION is offering sequential testing for neuropathies and a few
other labs offer a small subgroup of the ‘core’ genes (PMP22,
GJB1, MPZ).
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”.
Approval Date: Sept 2012
Submitting Laboratory: Bristol RGC
Copyright UKGTN © 2012
EPIDEMIOLOGY
Charcot-Marie-Tooth (CMT) hereditary neuropathy is the
most common genetic cause of neuropathy. Prevalence is
estimated to about 1:2,500 to 1:3,300 [1, 2].
In most North European countries, including the UK,
approximately 90% of the cases are AD or X-linked. In
populations with high rate of consanguineous marriages the
AR forms can account up to 40% [3].
The UK birth rate is approx 700,000 per year; with an
average disease prevalence of 1:3,000 it is estimated to have
200-250 new cases every year. Some will be severe early
onset and some adult late onset; usually CMT1 cases tend to
be of earlier onset compared to CMT2 cases.
CMT1 accounts for approximately 70% of the cases, and it is
more common than CMT2 (30%), while the prevalence of the
most subtypes of CMT1 and 2 is currently unknown [2, 4].
Table 1 presents the frequency data available for each
phenotypic subgroup.
The estimated prevalence of rare inherited neuropathies in
England is between 1.6 and 2.5/100,000 (800 to 1250
patients in England) [4-11]. This would include patients with
rare forms of CMT1, CMT2, HSN and dHMN. With more than
50 causative genes described most of these genes have only
been described in a limited number of cases and indeed
some of the genes have only been described in individual
families.
19. Estimated prevalence of
condition in the general UK
population
Please identify the information on
which this is based
References
1. Barisic N et al. Ann Hum Genet 72 (Pt3): 416-441, 2008
2.GeneReviews http://www.ncbi.nlm.nih.gov/books/NBK1358/
3. Dubourg O et al. Neuromolecular Med 8 (1-2): 75-86, 2009
4. Reilly MM et al Ann Indian Acad Neurol 12:80-88, 2009
5. Davis et al. J Gen Hum 26: 311-349; 1978
6. Brooks et al. J Med Genet 19: 88-93; 1982
7. MacMillan et al. Clin Genet 45: 128-134; 1994
8. MacDonald et al. Brain 123: 665-676; 2000
9. Dyck et al. Ann Neurol 10: 222-226; 1981
10. Harding and Thomas. Brain 103: 259-280; 1980
11. Szigeti et al. Genetics in Medicine 8: 86-92; 2006
20. Estimated gene frequency
(Carrier frequency or allele frequency)
Please identify the information on
which this is based
21. Estimated penetrance
Please identify the information on
which this is based
Approval Date: Sept 2012
Heterozygous gene frequency is estimated as the prevalence
for the autosomal dominantly inherited cases, this is up to
90% of all cases.
With an estimated maximum prevalence for any rare
recessive form of CMT1 as 1.5/100,000; a maximum gene
frequency of <1/250 would apply (<1/125 for carrier
frequency). However, for most of these the individual gene
frequencies are likely to be much lower.
Clinical penetrance is usually nearly complete; however,
some subtypes of CMT2 are associated with adult onset of
symptoms [1].
Mutations in the common genes are well characterised and
associated with the disease [2].
With the heterogeneity observed in inherited neuropathies,
with mutations in the same gene giving different phenotypes
and /or modes of inheritance, due for example to gain or loss
Submitting Laboratory: Bristol RGC
Copyright UKGTN © 2012
of function mutations, it is expected that there are some
mutations with incomplete penetrance. For example, in distal
HMN5, one mutation in GARS (G526R) has been found in
clinical asymptomatic carriers [3], suggesting incomplete
penetrance. In another CMT2C family, one TRPV4 mutation
(R315W) has been described with 4 variable phenotypes and
one unaffected member [4]. Overall, the evidence in the
literature is very limited, as most of these genes have been
studied in one or very few families.
There will be cases of detecting novel, previously
uncharacterised variants; these will need to be evaluated for
their clinical significance. Data from our three year audit
showed 81 variants (known polymorphisms excluded)
detected in 488 tests in 7 genes. From these 81 variants, 37
were known pathogenic mutations and 44 novel sequence
changes. Following bioinformatics analysis and family studies
where possible, from these 44, 23 were characterised as
pathogenic mutations and 13 as benign polymorphisms; only
8 remained unclassified.
Sorting out benign and causative variants represents one of
the major challenges of the new technologies and is an
ongoing progress in our laboratory but also in the clinical and
scientific community. A combination of informatics for
genetics analysis tools and family studies will be performed
for these variants as appropriate. Based on our so far
experience, it is expected that a high proportion of the initially
unclassified variants will be classified either as pathogenic or
polymorphic findings.
1.
2.
3.
4.
22. Estimated prevalence of
condition in the target population.
The target population is the group of
people that meet the minimum criteria
as listed in the Testing Criteria.
Gene Reviews: http://www.ncbi.nlm.nih.gov/books/NBK1358/)
IPN database: http://www.molgen.ua.ac.be/CMTMutations/
Dubourg, O et al, Neurology 66: 1721-1726, 2006
Arahoni et al. Am J Med Genet Part A 155-3153-3156, 2011
Target population
a) Patients with CMT1- including X linked and recessive
forms
b) Patients with CMT2
c) Patients with Intermediate CMT
d) Patients with Hereditary motor neuropathies
e) Patients with Hereditary sensory neuropathies
f) CMT can be suspected in patients with idiopathic
progressive peripheral neuropathy without other obvious
cause (eg. diabetes, B12 deficiency, alcohol abuse, CNS
demyelination or leukodystrophy), and particularly where
there is a similar family history
INTENDED USE
23. Please tick the relevant clinical purpose of testing
Diagnosis
Yes
No
Treatment
Yes
No
Prognosis & management
Yes
No
Presymptomatic testing
Yes
No
Carrier testing for family members
Yes
No
Prenatal testing
Yes
No
Approval Date: Sept 2012
Submitting Laboratory: Bristol RGC
Copyright UKGTN © 2012
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.
Analytical sensitivity:
22/22 SNPS (including missense, silent and intronic variants) previously identified with Sanger
sequencing were all correctly detected, suggesting a sensitivity of 100%
As the pilot project demonstrated that all previously known mutations and polymorphisms were
detected, we expect that using the same quality parameters if a mutation is present in a gene it will be
detected.
Analytical specificity
The bioinformatics pipeline used demonstrated that with appropriate filtering only the potentially
pathogenic variants are extracted. 7/8 previously diagnosed patients had a potentially pathogenic
variant confirmed by Sanger sequencing indicating an analytical specificity of 100%. Family segregation
studies are ongoing.
One of the eight patients had two candidate mutations; this is not surprising as the disease is
heterogenic and very little is known for genetic factors contributing to the variability of the clinical
phenotype. Segregation studies are likely to clarify this situation.
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 disease is known to be absent. The denominator in this case is the
number with the disease (for sensitivity) or the number without condition (for specificity).
From the 8 patients with unknown genetic cause, 7 obtained a potential genetic diagnosis using this
test in the pilot validation study. This is very promising, but we are unable to extrapolate these figures to
a clinical sensitivity as the cohort is small and had been very carefully selected. We are also aware that
a number of these genes have never been tested on a routine basis and accurate data is not available.
The detection of unclassified variants can potentially have an impact on the specificity of the test.
Informatics tools to assess pathogenicity and the increased data population of dbSNP from the 1000
genome data (and other big genome projects) are currently in use in the laboratory for assessing novel
variants. Segregation studies will assist. It is inevitable that some patients will have variants that are
unable to be classified as Pathogenic or non pathogenic using NGS gene panel technology. The
management of these issues is being addressed through best practice meetings organised by the
CMGS professional body in July. BGL will be participating in these discussions.
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).
For index cases:
Positive Predictive Value (PPV)= 100% for consensus mutations
Negative Predictive Value (NPV) = this is not possible to estimate as currently there is no diagnostic
service provided for the full selection of genes associated with a particular neuropathy sub-phenotype.
For testing family members, PPV and NPV are both effectively 100% for predisposition for symptoms
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.
Tests for genes associated with peripheral neuropathy are managed by clinical geneticists and
neurologists, and referrals can only be accepted from these specialties.
Patient samples (for index cases) can only be accepted for testing with confirmation (eg. on the request
form) that nerve conduction studies have been performed, and confirm a neuropathy. Pedigree
structure must also conform to the testing criteria. Additional clinical genetic advice is available locally
through the paediatric and adult neuromuscular and genetic services based in Bristol (eg. currently Dr
Approval Date: Sept 2012
Submitting Laboratory: Bristol RGC
Copyright UKGTN © 2012
Merrison, Dr Majumdar, Dr Lunt). Depending on the phenotype, the genes are grouped and will be
prioritised for analysis as shown below.
CMT1 AD or XL or sporadic
17p11.2 duplication
1A
1B
1C
1D
1E/and deafness
1F/2E
CMTX1
CMTX5
4A
4B1
4B2
4C
PMP22
MPZ
LITAF
EGR2
(PMP22)
NEFL
GJB1
PRPS1
AR - sporadic
GDAP1
MTMR2
SBF2
SH3TC2
4D
NDRG1
4E/CH
4F/DSS
4H
4J
(EGR2)
PRX
FGD4
FIG4
slowed NCV;
hypomyelination
CMT2 AD or sporadic
2A1
KIF1B
2A2
MFN2
2B/HSN
RAB7
2B1
LMNA
2B2
MED25
2C
TRPV4
2E/1F
NEFL
2F
HSPB1
2H
GDAP1
2I
MPZ
2J
MPZ
2K
GDAP1
2L
HSPB8
2N
AARS
2D
GARS
CMT2O DYNC1H1
CMT DI B/CMT 2M
CMT DI C
CMT DI D
CMT RI B
DNM2
YARS
(MPZ)
KARS
Hereditary Motor Neuropathy
HMN2B
HSPB1
HMN2C
HSPB3
HMN2A
HSPB8
HMN5 (dSMA V)
GARS
HMN5
BSCL2
HMN6 IGHMBP2
HMN7B
DCTN1
dSMA 4 PLEKHG5
dSMAX3
ATP7A
Hereditary Sensory Neuropathy
HSAN1 SPTLC1
HSAN1C SPTLC2
HSAN2A
WNK1
HSAN2B FAM134B
HSAN3 (Riley-Day syndrome)
HSAN4;anhidrosis, insensitivity to pain
HSN1D
HSAN5, absence of pain
HSN with spastic paraplegia
hereditary neuralgic amyotrophy, HNS,
HNA & symorphic features
ARHGEF10
absence of pain
Additional phenotypes
small fiber neuropathy
Giant Axonal Neuropathy 1
NTRK1
ATL1
NGFB
CCT5
SEPT9
SCN9A
SCN9A
GAN
PN with agenesis of the corpus callosum
SLC12A6
PCWH syndrome
SOX10
HMSN with Congenital vertical talus (1 italian descent family)
HOXD10
Congenital cataracts, facial dysmorphism, neuropathy
CTDP1
Spinocerebellar ataxia, rec with axonal neuropathy SCAN1
TDP1
Distal myopathy; myofibrillar, BAG-3 related; cardiomyopathy dilated
IKBKAP
BAG3
CLINICAL UTILITY
28. How will the test add to the management of the patient or alter clinical outcome?
Tests for genes associated with peripheral neuropathy are managed by clinical geneticists and
neurologists, and will assist in clinical and genetic management of those patients and their families. In
particular:
i) in defining the diagnosis it will avoid duplication of clinical investigation (which can be unpleasant)
in several other affected or equivocally affected family members
ii) The result facilitates prognostic prediction, and enables genetic testing for other family members to
help inform career, reproductive and other life decisions.
Clinical testing criteria will be applied as indicated, and summarised at end of dossier, for the defined
target population.
The application of NGS for IPN has been discussed with the local neurologists, and received with great
interest. The Paediatric Neurologist lead for the South West Interest in Muscle Groups (SWIM), and the
Approval Date: Sept 2012
Submitting Laboratory: Bristol RGC
Copyright UKGTN © 2012
Adult Neurology lead for the Neuromuscular Disease Service in the South West are supportive of this
application.
Testing will be therefore offered where it may:
1. Confirm diagnosis
2. Enable prognostic prediction and appropriate planning of clinical and lifestyle management
3. Establish inheritance pattern (as autosomal dominant, recessive, or X-linked) and hence provide
accurate advice on genetic risk)
4. Enable prenatal diagnosis where this is requested
There is no definitive alternative diagnostic means, as even characteristic nerve pathology does not
confirm the specific diagnostic subtype. There are no alternative biochemical tests. Genetic analysis is
becoming more the key to accurate diagnosis and management of this complex and heterogeneous
group of disorders.
29. How will the availability of this test impact on patient and family life?
No further investigations will be required. A positive result from the genetic analysis will confirm the
clinical diagnosis and eliminate the need for nerve biopsy on the basis that the clinical and
neurophysiological investigation is, together with family history, sufficiently suggestive of a particular
neuropathy phenotype.
A molecular diagnosis in one family member will help avoid unnecessary duplication of clinical and
primary molecular investigation of other family members (e.g. nerve conduction studies, EMG, nerve
biopsy, and testing for the same genes previously tested in the index case) – particularly where there
is an extensive dominant family history.
The availability of a definitive mutational diagnosis in a family will allow reproductive choice, and
anticipated future expansion of PGD (Pre-implantation diagnosis) as a means of avoidance of passing
on the condition to offspring.
30. Benefits of the test
There is no definitive alternative diagnostic means, as even characteristic nerve pathology does not
confirm the specific diagnostic subtype. There are no alternative biochemical tests. Genetic analysis is
becoming more the key to accurate diagnosis and management of this complex and heterogeneous
group of disorders.
A benefit of this panel approach to testing is the improved diagnosis rate as a number of patients in the
target population for this testing would be unlikely to arrive at the correct test using a sequential
approach due to limited resources.
A case that illustrates the above is the result of one of the eight patients from the pilot project. The
finding was a pathogenic EGR2 mutation in a patient who had not previously been tested for this gene
(which is available in our lab), as onset of his neuropathy was milder and much later in childhood than
the severe early childhood onset required. The phenotype of this patient might not have suggested
testing this gene singly but the broader criteria for the panel test would have ensured that they got the
correct diagnosis. . This approach overcomes the limitation imposed by basing testing decisions on the
limited available data of genotype-phenotype, especially for these rare genes.
No further diagnostic investigations will be required.
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.
No, not for definitive classification as a hereditary peripheral neuropathy. See above.
Approval Date: Sept 2012
Submitting Laboratory: Bristol RGC
Copyright UKGTN © 2012
32. Please describe any specific ethical, legal or social issues with this particular test.
Testing should only be performed when the patient (or their legal guardian) have understood and
consent to this test. Testing should be performed based on the clinical criteria described in the proforma
being met.
33. The Testing Criteria must be completed where Testing Criteria are not already available.
If Testing Criteria are available, do you agree with them
Yes/No
If No: Please propose alternative Testing Criteria AND please explain here the reasons for the
changes.
34. Savings or investment per annum in the diagnostic pathway based on national expected
activity, cost of diagnostics avoided and cost of genetic test.
Please show calculations.
The current strategy for testing when there is clinical evidence of CMT disease (ie CMT1) is dosage
analysis with MLPA for the common 17p11.2 duplication, and if this is negative proceed on to
sequential testing of the few genes that are diagnostically available. Similarly, if there is a clinical
diagnosis of axonal neuropathy (CMT2) the screening will start with mitofusin and then a few more
genes will be screened, depending on the specifics of the phenotype. Due to heterogeneity observed in
neuropathies, it is often very unclear which is the best place to start, there are mixed phenotypes and
there are other even more rare genes that have been associated with a particular phenotype but no
testing is available, due to their rarity and the expense of setting up testing for very rare genes (ie
KIF1B is consisted of 54 exons; besides its association with axonal neuropathy
(http://www.ncbi.nlm.nih.gov/books/NBK1511/) there is no UK service available)
A typical case of CMT type 1 negative for the PMP22 duplication, with the present sequential testing will
be tested for a total of the 7 genes currently in service (PMP22, MPZ, GJB1, NEFL, LITAF, EGR2,
PRX). This testing currently costs approx. £2,500 and would take up to one year to complete (8 weeks
x 7 genes = 56 weeks). With the NGS approach, we can test simultaneously for more genes (16) with
much less cost (£1,000) and significantly quicker result (12 weeks).
A presentation comparing the current and the NGS approach for each referral pathway is presented in
the following table.
Shown below are potential cost savings if clinical practice changed in all non-genetics specialties.
Savings are based on those made due to a move from sequencing individual genes to a NGS panel
approach. They are for illustrative purposes only.
CMT1
100 x £6200 = £620,000 (tests/procedures no longer required)
100 x £2500 = £250,000 (DNA tests carried out sequentially)
Total = £870,000
Minus costs of 100 panel tests £1000 each (£100,000)
Total annual savings = £770,000
CMT2
80 x £6200 = £496,000 (tests/procedures no longer required)
80 x £3200 = £256,000 (DNA tests carried out sequentially)
Total = £752,000
Minus cost of 80 panel tests £1000 each (£80,000)
Total annual savings = £672,000
Approval Date: Sept 2012
Submitting Laboratory: Bristol RGC
Copyright UKGTN © 2012
35. List the diagnostic tests/procedures that would no longer be required with costs.
C M T 1 test in g p ath w ay
N GS
cu r re n t
PM P2 2
v
v
M PZ
v
v
LI T AF
EG R2
N EF L
GJ B1
GD AP 1
PR X
PR PS 1
M TM R 2
SB F2
SH 3T C 2
N DR G 1
v
v
v
v
v
v
F GD 4
F IG 4
AR H GE F 10
T AT
C OS T
>1 y ea r
£2 ,5 00
v
v
v
v
v
v
v
v
v
v
v
v
v
v
C M T 2 te stin g p a th wa y
N GS
cu r re n t
v
v
MFN2
R A B7
L MN A
NE FL
H S PB 1
G D AP 1
MPZ
H S PB 8
D Y N C1 H 1
K IF 1 B
M E D 25
T R P V4
A AR S
G AR S
DNM2
Y AR S
K AR S
T AT
12 w ee ks
£ 1, 000
C OST
v
v
v
v
v
v
v
v
v
v
v
v
v
v
v
v
v
v
v
v
v
v
v
v
> 1. 5 y rs
£3, 20 0
12 w ee k s
£1,00 0
H M N te sti n g p a th wa y
v
v
H S PB 1
v
v
H S PB 8
v
v
B SC L 2
I G H M BP 2
H S PB 3
G AR S
DCTN1
P LE KH G 5
A T P7 A
T AT
C OS T
v
v
v
v
v
v
v
32 w e ek s 12 w ee k s
£1, 50 0
£1,00 0
H S(A )N tes tin g p ath w ay
v
v
S PT L C 1
v
v
IK BK AP
v
v
v
v
v
v
v
v
v
S PT L C 2
W N K1
F A M 134 B
NTRK 1
A T L1
NG FB
CCT5
S EP T 9
S C N 9A
T AT
CO ST
16 we ek s
£1, 00 0
12 w e ek s
£1, 00 0
The cost below is representative for all four different pathways.
Costs and type of imaging procedures
Costs and types of laboratory pathology tests
(other than molecular/cyto genetic proposed in this gene dossier)
Costs and types of physiological tests (e.g. ECG)
Cost and types of other investigations/procedures (e.g. biopsy)
Cost outpatient consultations (genetics and non genetics)
Total cost tests/procedures no longer required
Approval Date: Sept 2012
MRI brain x1 ~ £ 1000
Biochem etc £ 300 x 3
DNA on other fam. (£500)
Total £1400
E-physiol on fam memb £ 250 x2
= £500
Muscle biopsy £1000
Nerve biopsy 1000
Genetic consult (x2) £ 800
Neurology consult (x2) £ 500
Total : £1300
£ 6200
Submitting Laboratory: Bristol RGC
Copyright UKGTN © 2012
36. REAL LIFE CASE STUDY
In collaboration with the clinical lead, describe a real case example to illustrate how the
test would improve patient experience.
A female patient (III-2), currently 24 years old, presented at age 9yrs with bilateral pes cavus and gait
abnormality. Her mobility gradually worsened; and she was diagnosed with axonal neuropathy, with
intermediate NCVs (35 to 42 m/s). Her father (II-1), who had died at age 30 yrs from respiratory failure
and possible cardiomyopathy, had been diagnosed earlier in life with HMSN 1 on the basis of distal
weakness, congenital talipes, and e-physiology showing slowed NCV (<38m/s). At age 20 years he
had developed respiratory difficulty, requiring ventilatory support, and may have developed a
subsequent cardiomyopathy. There was also a past family history of hypertrophic cardiomyopathy in a
paternal great aunt (I-1), and it was considered that this might be a separate condition, but potentially
hereditary autosomal dominant, from the apparent hereditary peripheral neuropathy.
A series of genetic testing had been sequentially performed on both!!-2 (17p11.2, PMP22, MPZ, MFN2,
NEFL, GDAP1) and on a stored DNA sample from her father (17p11.2, GJB1, Dystrophin, Myotonic
dyst.), in order to elucidate the cause and be able to offer genetic advice (III-2 already had a young
daughter, and there had been enquiry from an elder clinically unaffected sister), but no mutation was
found.
III-2 has a seven years younger sister (III-1), with bilateral progressive pes cavus, mobility difficulties,
and similar e-physiology studies as her sister. However by age 14 years III-2 had developed a scoliosis
and a restrictive cardiomyopathy, and the possibility of a myofibrillar myopathy to link the
cardiomyopathy with distal weakness was considered.
Recently DNA analysis has revealed a mutation in BAG3 in the affected sister III-1 (p.Pro209Leu). This
is consistent with the clinical phenotype of distal weakness, and cardiomyopathy. Mutations in BAG3
have been associated with childhood-onset of rapidly progressive myofibrillar myopathy and with
autosomal dominant dilated cardiomyopathy. The electrophysiology findings indicating the peripheral
neuropathy are of interest, but undoubtedly will be part of the clinical manifestation. Other family
members can now be tested for the BAG3 mutation and a care pathway can be decided accordingly.
For III-2 this information can enable cardiorespiratory monitoring and preventative medical
management, but with possible more radical treatments if the clinical situation deteriorates. Currently
she has also developed some respiratory problems in the past 2 years. More generally, since the initial
presentation and investigations in the family was for a hereditary peripheral neuropathy we are
including this gene in our panel. Had NGS been available at the outset it would have identified the
cardiomyopathy and respiratory risk at an early stage, and enabled medical management and
surveillance to prevent or delay these complications, including the possible future requirement for
consideration of cardiac transplant. It would also of course have saved the cost of the sequential
investigation on both father and daughter.
The cost of genetic testing only, (excluding the BAG3 gene which took place in the Mayo Clinic, USA as
it was not available in the UK), exceeds £ 3,300 (II1 > £800, III2 > £2,500). Additionally, all the affected
members of this family have been seen for diagnostic consideration by numerous paediatricians,
clinical geneticists, neurologists, orthopaedic surgeons, and cardiologists in the course of 15 years.
The costs for clinical management will stand the same, except that earlier diagnosis and preventative
measures may save on overall costs, particularly if (say) cardiac transplantation may now be under
consideration at an earlier age than would have been the case with preventative measures.
Approval Date: Sept 2012
Submitting Laboratory: Bristol RGC
Copyright UKGTN © 2012
I
1
Hypertrophic
Cardiomyopathy
II
HMSN 1
?cardiomyopathy/
dilated? /hypertrophic
respiratory problems
III
bilateral pes cavus 1
mobility difficulties
myofibrillar myopathy
severe scoliosis
restrictive cardiomyopathy
2
bilateral pes cavus
axonal neuropathy
mobility difficulties
respiratory problems
IV
4
epilepsy
no motor problems
37. For the case example, if there are cost savings, please provide these below:
PRE GENETIC TEST
Costs and type of imaging procedures
Extra cardiac etc. due to earlier disease
Costs and type of laboratory pathology tests
(other than molecular/cyto genetic proposed in this gene dossier)
Costs and type of physiological tests (e.g. ECG)
Extra Nerve Conduction /EMG
Cost and type of other investigations/procedures (e.g. biopsy) Muscle /nerve
Cost outpatient consultations (genetics and non genetics)
Diagnostic x 10
Total cost pre genetic test
£1000
£300x 10-12 =
£4000
£200 x 4=
£800
£500
@£ 200-400 x10
£3000
TOTAL £ 9300
Plus cost of earlier
heart transplant if
required (? £20,000)
POST GENETIC TEST
Costs and type of imaging procedures
Cardiac
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)
Resp /cardiac
Cost and type of other investigations/procedures (e.g. biopsy)
Cost outpatient consultations (genetics and non genetics)
Total cost post genetic test
£500
£1000
£500
£1000
£3000
38. Estimated savings for case example described £9,300 - £3,000 = £6,300
Approval Date: Sept 2012
Submitting Laboratory: Bristol RGC
Copyright UKGTN © 2012
UKGTN Testing Criteria
Approved name and symbol of disease/condition(s):
Charcot-Marie-Tooth Hereditary Neuropathy
Hereditary Motor Neuropathy
Hereditary Sensory Autonomic Neuropathy
Approved name and symbol of gene(s):
See Table 2
OMIM number(s):
See Table 1
OMIM number(s):
See Table 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 Neurologist or Paediatric Neurologist
Consultant Clinical Geneticist
Minimum criteria required for testing to be appropriate as stated in the Gene Dossier:
Criteria
‘Idiopathic’ peripheral neuropathy diagnosed by :
1. Clinical presentation with progressive weakness in hands/wrists and/or feet/ankles
AND/OR associated pes cavus or finger flexion contractures AND/OR peripheral
sensory loss
AND
2. Supportive nerve conduction test result (defining type I or II according to NCV)
AND
3. Absence of other non-genetic causes (alcohol, B12 defy, diabetes, trauma)
AND
4. No associated CNS involvement
… giving diagnosis as one of:
Demyelinating neuropathy AD or AR or X-Linked
Axonal neuropathy AD or AR or intermediate
Motor Neuropathy AD or AR
Tick if
this
patient
meets
criteria
OR
OR
OR
Sensory neuropathy AD or AR
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 2012
Submitting Laboratory: Bristol RGC
Copyright UKGTN © 2012
Table 1
recessive forms
Intermediate
forms
CMT type 2
CMT type 1
Phenotype
H
S
A
N
HMN
X-linked
Disease MIM
Gene
Gene MIM
Inheritance
Frequency
per specific type
(1A, 1B etc)
601097
AD
70-80%
118200
PMP22
(duplication)
MPZ
159440
AD
10-12%
601098
LITAF
603795
AD
1-2%
1D
607678
129010
AD
<2%
1E/and deafness
118300
601097
AD
<5%
162280
AD
<5%
605995
AD
1A
118220
1B
1C
1F/2E
607734
EGR2
PMP22
(point
mutations)
NEFL
2A1
118210
KIF1B
2A2
609260
MFN2
608507
AD
2B/HSN
600882
RAB7
602298
AD
2B1
605588
LMNA
150330
AD, AR
2B2
605598
MED25
610197
AD
2C
606071
TRPV4
605427
AD
2E/1F
607684
NEFL
162280
AD
2F
606595
HSPB1
602195
AD
2H
607731
GDAP1
606598
AD
2I
607677
MPZ
159440
AD
2J
607736
MPZ
159440
AD
2K
607831
GDAP1
606598
AD
2L
608673
HSPB8
608014
AD
2N
613287
AARS
601065
AD
2D
601472
GARS
600287
AD
CMT2O
614228
DYNC1H1
600112
AD
CMT DI B/CMT 2M
606482
DNM2
602378
AD
CMT DI C
608323
YARS
603623
AD
CMT DI D
607791
MPZ
159440
AD
AR
CMT RI B
613641
KARS
601421
4A
214400
GDAP1
606598
AR
4B1
601382
MTMR2
603557
AR
4B2
604563
SBF2
607697
AR
4C
601596
SH3TC2
608206
AR
4D
601455
NDRG1
605262
AR
4E/CH
605253
EGR2
129010
AR
4F/DSS
145900
PRX
605725
AR
4H
609311
FGD4
611104
AR
4J
611228
FIG4
609390
AR
CMTX1
302800
GJB1
304040
XL
CMTX5
311070
PRPS1
311850
XL
HMN2B
608634
HSPB1
602195
AD
HMN2C
613376
HSPB3
604624
AD
HMN2A
158590
HSPB8
608014
AD
HMN5 (dSMA V)
600794
GARS
600287
AD
HMN5
600794
BSCL2
606158
AD
HMN6
604320
IGHMBP2
600502
AR
HMN7B
607641
DCTN1
601143
AD
dSMA 4
611067
PLEKHG5
611101
AR
dSMAX3
300489
ATP7A
300011
XL
HSAN1
162400
SPTLC1
605712
AD
Approval Date: Sept 2012
20%
<5%
5%
3%
90%
Submitting Laboratory: Bristol RGC
Copyright UKGTN © 2012
HSAN1C
613640
SPTLC2
605713
AD
HSAN2A
201300
WNK1
605232
AR
HSAN2B
613115
FAM134B
613114
AR
HSAN3 (Riley-Day
syndrome)
223900
IKBKAP
603722
AR
HSAN4;anhidrosis,
insensitivity to pain
256800
NTRK1
191315
AR
613708
ATL1
606439
AD
608654
NGFB
152030
AR
256840
CCT5
610150
AR
608236
ARHGEF10
608136
AD
162100
SEPT9
604061
AD
243000
SCN9A
603415
AR
small fiber neuropathy
Giant Axonal
Neuropathy 1
PN with agenesis of
the corpus callosum
133020
SCN9A
603415
AD
256850
GAN
605379
AR
218000
SLC12A6
604878
AR
PCWH syndrome
609136
SOX10
602229
AD
192950
HOXD10
142984
AD
604168
CTDP1
604927
AD
607250
TDP1
607198
AR
rare forms with additional features
HSN1D
HSAN5, absence of
pain
HSN with spastic
paraplegia
slowed NCV;
hypomyelination
hereditary neuralgic
amyotrophy,HNS,
HNA & symorphic
features
absence of pain
HMSN with Congenital
vertical talus
Congenital cataracts,
facial dysmorphism,
neuropathy
Spinocerebellar
ataxia, rec with axonal
neuropathy SCAN1
distal myopathy;
myofibrillar, BAG-3
related;
cardiomyopathy
dilated, but with ephysiol evidence of
Neuropathy
Approval Date: Sept 2012
612954/
613881
BAG3
603883
AD
Submitting Laboratory: Bristol RGC
Copyright UKGTN © 2012
Table 2
Approved gene
symbol
MIM
Approved Name
exons/ROI
AARS
601065
Alanyl-tRNA synthetase
ARHGEF10
ATL1
608136
606439
Rho guanine nucleotide exchange factor (GEF) 10
Atlastin GTPase 1
ATP7A
BAG3
300011
603883
ATPase, Cu++transporting, alpha polypeptide
BSCL2
CCT5
606158
610150
CTDP1
604927
DCTN1
601143
BCL2-associated athanogene 3
Berardinelli-Seip congenital lipodystrophy 2 (seipin)
Chaperonin containing TCP1, subunit 5 (epsilon)
CTD (carboxy-terminal domain, RNA polymerase II, polypeptide A) phosphatase, subunit
1
Dynactin 1
21
30
19
22
4
15
12
13
39
DNM2
602378
Dynamin 2
22
DYNC1H1
EGR2
600112
129010
Dynein, cytoplasmic 1, heavy chain 1
Early growth response 2
78
4
FAM134B
FGD4
613114
611104
Family with sequence similarity 134, member B
FYVE, RhoGEF and PH domain containing 4
10
24
FIG4
GAN
609390
605379
FIG4 homolog, SAC1 lipid phosphatase domain containing
Gigaxonin
25
4
GARS
600287
Glycyl-tRNA synthetase
19
GDAP1
GJB1
606598
304040
Ganglioside-induced differentiation-associated protein 1
Gap junction protein, beta 1
6
4
HOXD10
HSPB1
142984
602195
Homeobox 4D
Heat shock protein 1
2
HSPB3
HSPB8
604624
608014
Heat shock protein 27-like protein
Heat shock protein 8
1
5
IGHMBP2
600502
15
IKBKAP
603722
KARS
601421
Immunoglobulin mu binding protein 2
Inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase complex-associated
protein
Lysyl-tRNA synthetase
KIF1B
605995
Kinesin family member 1B
LITAF
LMNA
603795
150330
Lipopolysaccharide-induced TNF factor
Lamin A/C
MED25
MFN2
610197
608507
Mediator complex subunit 25
Mitofusin 2
19
20
MPZ
MTMR2
159440
603557
Myelin protein zero
Myotubularin related protein 2
6
21
NDRG1
605262
N-myc downstream regulated 1
NEFL
NGFB
162280
152030
Neurofilament, light polypeptide
Nerve growth factor beta
24
4
NTRK1
PLEKHG5
191315
611101
Neurotrophic tyrosine kinase, receptor, type 1
Pleckstrin homology domain containing, family G (with RhoGef domain) member 5
19
28
PMP22
PRPS1
601097
311850
Peripheral myelin protein 22
Phosphoribosyl pyrophosphate synthetase 1
7
7
6
6
2
38
15
54
6
19
3
PRX
605725
Periaxin
RAB7
SBF2
602298
607697
RAB7A, member RAS oncogene family
SET binding factor 2
41
SCN9A
SEPT9
603415
604061
Sodium channel, voltage-gated, type IX, alpha subunit
Septin 9
28
19
SH3TC2
SLC12A6
608206
604878
SH3 domain and tetratricopeptide repeats 2
Solute carrier family 12 (potassium/chloride transporters), member 6
20
28
6
16
SOX10
602229
SRY (sex determining region Y)-box 10
SPTLC1
SPTLC2
605712
605713
Serine palmitoyltransferase, long chain base subunit 1
Serine palmitoyltransferase, long chain base subunit 2
TDP1
TRPV4
607198
605427
Tyrosyl-DNA phosphodiesterase 1
Transient receptor potential cation channel, subfamily V, member 4
24
16
WNK1
YARS
605232
603623
WNK lysine deficient protein kinase 1
Tyrosyl-tRNA synthetase
33
13
Approval Date: Sept 2012
Submitting Laboratory: Bristol RGC
Copyright UKGTN © 2012
13