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PMP22-Related Neuropathies

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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TEST METHODS

Sequencing

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
2047 PMP22$540.00 81325 Add to Order
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 18 days.

Clinical Sensitivity

It is estimated that ~80% of individuals with clinical HNPP have the common 1.5 Mb deletion, while the remaining 20% have a different sequence variant within the PMP22 gene detectable by sequencing (Bird 2015). In a recent study of 100 Greek patients suspected to have HNPP, 54% were found to be positive for either the common 1.5 Mb deletion or a "micromutation". In the positive patients, 96% had the common deletion, while the other 4% had  sequence variants detectable by sequencing (Karadima et al. 2015). Another source cites that 85-90% of patients with clinical HNPP have the 1.5 Mb deletion (van Paassen et al. 2014). It is estimated that ~70% of all Charcot Marie Tooth Type 1 (CMT1) are due to the PMP22 1.5 Mb duplication, while only around 5% of CMT1 cases are due to point mutations (Bird 2015).

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 PMP22$690.00 81324 Add to Order
Pricing Comment

# of Genes Ordered

Total Price

1

$690

2

$730

3

$770

4-10

$840

11-30

$1,290

31-100

$1,670

Over 100

Call for quote

Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Sensitivity

In about 80% of patients with HNPP, the most common pathogenic variant is a 1.5 Mb deletion of chromosome 17p11.2 (Bird 2015). Another source cites that 85-90% of patients with clinical HNPP have the 1.5 Mb deletion (van Paassen et al. 2014). Approximately 70% of CMT1 is caused by the recurrent PMP22 duplication (Bird 2015; Li et al. 2013; van Paassen et al. 2014).

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Clinical Features

PMP22-related neuropathies can be grouped into three different categories: Hereditary neuropathy with liability to pressure palsies commonly caused by a PMP22 deletion, Charcot Marie Tooth 1A caused by a PMP22 duplication, and Charcot Marie Tooth 1E due to various other pathogenic sequence variants.

Hereditary neuropathy with liability to pressure palsies (HNPP) is characterized by recurrent sensory and motor neuropathy in a single nerve. The most vulnerable nerves are the peroneal and ulnar, followed by the brachial plexus nerve, radial nerve, and median nerve. Common symptoms include focal numbness, muscular weakness, atrophy, pes cavus, and reduced/absent tendon reflexes. Nerve conduction studies typically show prolongation of distal nerve conduction latencies and focal slowing of conduction velocity at the site of compression. The presence of tomacula structures in the peripheral nerve myelin from sural nerve biopsies is a classic pathological feature. Onset is normally in the second or third decade. However, the age range of presentation is 2-70 years (Li et al. 2013; van Paassen et al. 2014; Bird 2015; Lupski and Garcia 2014; Wiszniewski et al. 2013).

Charcot Marie Tooth 1A (CMT1A) is the most common form of CMT1. Age of onset is usually within the first two decades, and many individuals present in the first 10 years of life. Typically, presentation includes difficulty in walking or running, weakness of the distal leg muscles, sensory loss, and slow nerve conduction velocity (less than 38m/s). Distal muscle weakness and wasting is normally symmetrical with legs being more severely affected than upper extremities. Pes cavus and hammertoes are cardinal features of CMT1A. Phenotype variability is common with some patients having a severe phenotype in infancy while others are only minimally disabled through life (Li et al. 2013; van Paassen et al. 2014; Bird 2015; Lupski and Garcia 2014; Wiszniewski et al. 2013) .

Charcot Marie Tooth 1E (CMT1E) often presents similarly to other subtypes of CMT1. Depending on the pathogenic variant, patients can present with classic CMT or HNPP or even an overlap between the two phenotypes. Some patients present with a mild HNPP-like neuropathy while others have a severe early onset dysmyelinating neuropathy like Dejerine-Sottas disease. Patients present with impaired motor development, distal muscle weakness, foot deformities, and loss of deep tendon reflex. Sensory deficits have also been observed. In a small subset of CMT1E patients, clinical symptoms have been suggestive of an axonal neuropathy (Li et al. 2013; van Paassen et al. 2014; Bird 2015; Lupski and Garcia 2014; Wiszniewski et al. 2013).

Genetics

HNPP is inherited in an autosomal dominant manner. In about 80% of patients with HNPP, the most common pathogenic variant is a 1.5 Mb deletion of chromosome 17p11.2 (Bird 2015). In the remaining 20% of patients with HNPP, single nucleotide variants such as missense, nonsense, splicing, and small insertions/deletions detectable by sequencing have been reported (Human Gene Mutation Database; Bird 2015). Prevalence is estimated to be 7.3:100,000 to 16:100,000 (Bird 2015; Li et al. 2013; van Paassen et al. 2014).

CMT1A is inherited in an autosomal dominant manner. CMT1A is most commonly caused by a 1.5 Mb duplication of chromosome 17p11.2 which includes PMP22. The duplication occurs due to unequal crossing over of homologous chromosomes at regions of repetitive elements. About one-third of these cases occur de novo. Other smaller duplications of the PMP22 gene have been reported in a few cases. Approximately 70% of CMT1 is caused by the recurrent PMP22 duplication (Bird 2015; Li et al. 2013; van Paassen et al. 2014).

CMT1E is inherited in an autosomal dominant manner and caused by sequence variants in the PMP22 gene. It is considered a rare subtype of CMT1 and estimated to account for 1-5% of CMT1 cases (Bird 2015; Li et al. 2013; van Paassen et al. 2014). Pathogenic variants include missense, nonsense, splicing, and small insertions/deletions (Human Gene Mutation Database).

Very rare autosomal recessive neuropathy (CMT4) caused by homozygosity for sequence variants in PMP22 has been reported.

The PMP22 gene encodes for the peripheral myelin protein-22 which is an integral membrane glycoprotein of the intermodal myelin. It is present in the compact myelin and has four transmembrane domains. Pathogenic variants in PMP22 lead to myelin disorganization and result in the PMP22-related neuropathies. PMP22-related neuropathies have variable expressivity and incomplete penetrance.

Testing Strategy

Testing involves PCR amplification from genomic DNA and bidirectional Sanger sequencing of the 4 coding exons in the PMP22 gene and ~20bp of adjacent noncoding sequences. This testing strategy will reveal coding sequence changes, splice site mutations and small insertions or deletions in the PMP22 gene, but will not detect the common large duplication or deletion. We will also sequence any single exon (Test #100) in family members of patients with known mutations or to confirm research results.

Indications for Test

Individuals with symptoms consistent with any of the PMP22-related neuropathies.

Gene

Official Gene Symbol OMIM ID
PMP22 601097
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Tests

Name
Charcot Marie Tooth - Comprehensive Sequencing Panel
Charcot Marie Tooth - Demyelinating Neuropathy Sequencing Panel
Comprehensive Neuropathy Sequencing Panel

CONTACTS

Genetic Counselors
Geneticist
Citations
  • Bird T.D. 2015. Charcot-Marie-Tooth Neuropathy Type 1. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 20301384
  • Bird TD. 2015. Hereditary Neuropathy with Liability to Pressure Palsies. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 20301566
  • Human Gene Mutation Database (Bio-base).
  • Karadima G, Koutsis G, Raftopoulou M, Karletidi K-M, Zambelis T, Karandreas N, Panas M. 2015. Mutational analysis of Greek patients with suspected hereditary neuropathy with liability to pressure palsies (HNPP): a 15-year experience. J. Peripher. Nerv. Syst. PubMed ID: 26110377
  • Li J. et al. 2013. Molecular Neurobiology. 47: 673-98. PubMed ID: 23224996
  • van Paassen BW, van der Kooi AJ, van Spaendonck-Zwarts KY, Verhamme C, Baas F, Visser M de. 2014. PMP22 related neuropathies: Charcot-Marie-Tooth disease type 1A and Hereditary Neuropathy with liability to Pressure Palsies. Orphanet journal of rare diseases 9: 38. PubMed ID: 24646194
Order Kits
TEST METHODS

Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (http://www.hgvs.org).  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 20 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of March 2016, we compared 17.37 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 12 years of our lab operation we have Sanger sequenced roughly 8,800 PCR amplicons. Only one error has been identified, and this was due to sequence analysis error.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 20 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Deletion/Duplication Testing Via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

Order Kits

Ordering Options


myPrevent - Online Ordering
  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
REQUISITION FORM
  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

SPECIMEN TYPES
WHOLE BLOOD

(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.

DNA

(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.

CELL CULTURE

(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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