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Increased Pain Sensitivity via the COMT Gene

  • 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
1803 COMT$610.00 81479 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
Because only 11 sequence variants have been registered in the Human Gene Mutation Database (Stenson et al. 2014), is difficult to estimate the clinical sensitivity of this test. Analytical sensitivity should be high because all pathogenic variants reported are detectable by sequencing.

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Clinical Features
Increased sensitivity to pain pertains to a chronic syndrome that is characterized by lowered thresholds for pain and other pain-related syndromes, including fibromyalgia, temporomandibular disorder, lower back pain due to disc herniation or sciatica, irritable bowel syndrome, anxiety, depression, fatigue, and postoperative pain (Finan et al. 2011; Karling et al. 2011; Gruber et al. 2014). Catechol-O-methyltransferase (COMT) is an enzyme that is involved in various physiological functions, including modulating pain sensitivity by degrading catecholamine neurotransmitters such as dopamine, noradrenaline, and adrenaline after these are released in the synaptic cleft (Júlio-Costa et al. 2013). A deficiency in COMT levels often results in enhanced activation of dopaminergic neurotransmission, with lower endogenous levels of enkephalins, which in turn results in exaggeration of pain sensitivity. Individuals with COMT deficiency thus present with higher sensory and affective ratings of pain, and a more negative affective response to sustained pain (Kilford et al. 2015). Clinical pain characteristics are usually determined by conducting various tests that estimate an individual's threshold for a particular type of stimulus that elicits pain, including touch sensitivity using von Frey monofilaments on skin, pressure pain using a digital dynamometer, and heat and cold pain using a thermal stimulator, as well as psychological open-ended questionnaires that consist of questions related to pain. Functional magnetic resonance imaging of the brain of individuals with increased sensitivity to pain generally show an increased in brain response to various kinds of stimuli (Viviani et al. 2014).
Genetics
Although certain environmental factors might play a role in the origin of development of increased sensitivity to pain, genetic factors have also been implicated in this disorder. Increased sensitivity to pain is caused by autosomal recessive, pathogenic sequence variants in the COMT gene, which encodes an enzyme that plays a major role in pain processing. The COMT gene consists of 6 exons and encodes a 24.4-kD polypeptide that is either secreted into the cytoplasm as a soluble enzyme (S-COMT) or integrated into the cellular membrane (MB-COMT) (Bertocci et al. 1991; Tenhunen et al. 1994). COMT has been localized to human chromosomal region 22q11.21.

To date, a total of 11 pathogenic sequence variants have been reported in the COMT gene, which include six missense/nonsense variants, four regulatory variants, and one complex rearrangement (Stenson et al. 2014). The COMT gene has also been implicated in inter-individual variations in the response of analgesics and other painkillers (Rakvåg et al. 2008).
Testing Strategy
Full gene sequencing of all 4 coding exons of the COMT gene is performed. The full coding region of each exon plus ~10 bp of flanking non-coding DNA on either side are sequenced. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known mutations or to confirm research results.
Indications for Test
Ideal COMT test candidates are individuals who show elevated sensitivity to pain, often affecting their quality of life (Sprangers et al. 2014). These individuals should have completed at least two assessments for pain threshold, namely, the pain questionnaire and one of the pain threshold assays (i.e., heat, cold, or pressure).

Gene

Official Gene Symbol OMIM ID
COMT 116790
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Panic Disorder 1 167870

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CONTACTS

Genetic Counselors
Geneticist
Citations
  • Bertocci B, Miggiano V, Da Prada M, Dembic Z, Lahm HW, Malherbe P. 1991. Human catechol-O-methyltransferase: cloning and expression of the membrane-associated form. Proceedings of the National Academy of Sciences USA 88(4): 1416-1420. PubMed ID: 1847521
  • Finan PH, Zautra AJ, Davis MC, Lemery-Chalfant K, Covault J, Tennen H. 2011. COMT moderates the relation of daily maladaptive coping and pain in fibromyalgia. Pain 152(2): 300-307. PubMed ID: 21130573
  • Gruber HE, Sha W, Brouwer CR, Steuerwald N, Hoelscher GL, Hanley EN Jr. 2014. A novel catechol-O-methyltransferase variant associated with human disc degeneration. International Journal of Medical Sciences 11(7): 748-753. PubMed ID: 24904231
  • Júlio-Costa A, Antunes AM, Lopes-Silva JB, Moreira BC, Vianna GS, Wood G, Carvalho MR, Haase VG. 2013. Count on dopamine: influences of COMT polymorphisms on numerical cognition. Frontiers in Psychology 4:531 PubMed ID: 23966969
  • Karling P, Danielsson Å, Wikgren M, Söderström I, Del-Favero J, Adolfsson R, Norrback KF. 2011. The relationship between the val158met catechol-O-methyltransferase (COMT) polymorphism and irritable bowel syndrome. PLoS One 6(3):e18035. PubMed ID: 21437260
  • Kilford EJ, Dumontheil I, Wood NW, Blakemore SJ. 2015. Influence of COMT genotype and affective distractors on the processing of self-generated thought. Social Cognitive and Affective Neuroscience 10(6):777-782, PubMed ID: 25190703
  • Rakvåg TT, Ross JR, Sato H, Skorpen F, Kaasa S, Klepstad P. 2008. Genetic variation in the catechol-O-methyltransferase (COMT) gene and morphine requirements in cancer patients with pain. Molecular Pain 4:64. PubMed ID: 19094200
  • Sprangers MA, Thong MS, Bartels M, Barsevick A, Ordoñana J, Shi Q, Wang XS, Klepstad P, Wierenga EA, Singh JA, Sloan JA; GeneQol Consortium. 2014. Biological pathways, candidate genes, and molecular markers associated with quality-of-life domains: an update. Quality of Life Research 23(7): 1997-2013. PubMed ID: 24604075
  • Stenson PD, Mort M, Ball EV, Shaw K, Phillips A, Cooper DN. 2014. The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Human Genetics 133(1): 1-9. PubMed ID: 24077912
  • Tenhunen J, Salminen M, Lundström K, Kiviluoto T, Savolainen R, Ulmanen I. 1994. Genomic organization of the human catechol O-methyltransferase gene and its expression from two distinct promoters. European Journal of Biochemistry 223(3): 1049-1059. PubMed ID: 8055944
  • Viviani R, Lehmann ML, Stingl JC. 2014. Use of magnetic resonance imaging in pharmacogenomics. British Journal of Clinical Pharmacology 77(4): 684-694. PubMed ID: 23802603
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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 10 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of February 2018, we compared 26.8 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 14 years of our lab operation we have Sanger sequenced roughly 14,300 PCR amplicons. Only one error has been identified, and this was an error in analysis of sequence data.

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 10 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.

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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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