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Carney Complex (CNC) via the PRKAR1A 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
1287 PRKAR1A$750.00 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

Pathogenic variants in the PRKAR1A gene can be detected via sequencing in ~60% of affected individuals (Stratakis and Horvath 2012).

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 PRKAR1A$690.00 81479 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

Pathogenic variants in the PRKAR1A gene can be detected via large deletion testing in 2-21% of affected individuals (Stratakis and Horvath 2012; Salpea et al. 2014).

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Clinical Features

Carney Complex (CNC) is a disorder that is characterized by skin pigment abnormalities, myxomas, endocrine overactivity or tumors, and schwannomas (Stratakis and Horvath 2012). This disorder had previously been called LAMB (lentigines, atrial myxomas, mucocutaneous myxomas, and blue naevi) or NAME (naevi, atrial myxomas, myxoid neurofibroma, and ephelides) (Rothenbuhler and Stratakis 2010). The most common skin pigment changes are lentigines, which are small benign pigmented spots on the skin with a clearly defined border. Both cutaneous and cardiac myxomas are also observed in individuals with CNC. Myxomas are tumors that are primarily connective tissue, which can occur in the skin, breast, oropharynx or the female genital tract. Cardiac myxomas occur at a young age and can obstruct blood flow leading to heart failure, and are one of the leading causes of CNC mortality. Other clinical manifestations of CNC include primary pigmented nodular adrenocortical disease (PPNAD), which is the most frequently observed tumor, found in approximately 25% of affected individuals. This causes periodic or atypical Cushing syndrome, where the body is exposed to prolonged exposure to cortisol leading to obesity, severe fatigue, weak muscles, high blood pressure, high blood sugar, irritability, and anxiety. Large-cell calcifying Sertoli cell tumors (LCCSCTs) are found in almost all adult males, and multiple thyroid nodules are identified in approximately 75% of affected individuals. Acromegaly resulting from a growth hormone (GH)-producing adenoma and Psammomatous melanotic schwannoma (PMS) are identified in approximately 10% of affected individuals (Halászlaki et al. 2012; Stratakis and Horvath 2012). The median age of diagnosis is 20 years, and more than 700 cases worldwide are known (Stratakis and Horvath 2012).

Genetics

Carney Complex (CNC) is an autosomal dominant disorder that has near complete penetrance by age 50 (Stratakis and Horvath 2012). It is caused by mutations in the PRKAR1A gene, which encodes a tumor suppressor that acts as a cyclic-AMP-dependent signaling molecule. The signaling molecule phosphorylates many downstream targets that are involved in transcription, metabolism, cell cycle progression and apoptosis (Rothenbuhler and Stratakis 2010). Approximately 70% of PRKAR1A causative mutations are inherited from an affected parent, and 30% of causative mutations are de novo. Most pathogenic variants result in protein loss of function, such as nonsense, and small insertions and deletions; causing nonsense mediated decay (Pan et al. 2010). Other causative mutations include missense variants and large deletions. Specific genotype-phenotype correlations have been observed with certain pathogenic variants, which may guide clinical management (Stratakis and Horvath 2012).

Testing Strategy

The cAMP-dependent protein kinase type I-alpha regulatory subunit is encoded by 10 exons (3-12) from the PRKAR1A gene on chromosome 17q23-q24. Testing is accomplished by amplifying each coding exon and ~20 bp of adjacent noncoding sequence, then determining the nucleotide sequence using standard Sanger dideoxy sequencing methods and a capillary electrophoresis instrument. We will also sequence any single exon (Test #100) in family members of patients with a known mutation or to confirm research results.

Indications for Test

Individuals with a clinical presentation of Carney Complex and individuals with a family history.

Gene

Official Gene Symbol OMIM ID
PRKAR1A 188830
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Tests

Name
Familial Isolated Pituitary Adenoma via the AIP Gene
Primary Macronodular Adrenal Hyperplasia via the ARMC5 Gene
Primary Pigmented Nodular Adrenocortical Disease via the PDE11A Gene

CONTACTS

Genetic Counselors
Geneticist
Citations
  • Halászlaki C, Takács I, Butz H, Patócs A, Lakatos P. 2012. Novel Genetic Mutation in the Background of Carney Complex. Pathology & Oncology Research 18: 149–152. PubMed ID: 22297707
  • Pan L, Peng L, Jean-Gilles J, Zhang X, Wieczorek R, Jain S, Levine V, Osman I, Prieto VG, Lee P. 2010. Novel PRKAR1A gene mutations in Carney Complex. International journal of clinical and experimental pathology 3: 545. PubMed ID: 20606737
  • Rothenbuhler A, Stratakis CA. 2010. Clinical and molecular genetics of Carney complex. Best Practice & Research Clinical Endocrinology & Metabolism 24: 389–399. PubMed ID: 20833331
  • Salpea P, Horvath A, London E, Faucz FR, Vetro A, Levy I, Gourgari E, Dauber A, Holm IA, Morrison PJ, Keil MF, Lyssikatos C, et al. 2014. Deletions of the PRKAR1A Locus at 17q24.2-q24.3 in Carney Complex: Genotype-Phenotype Correlations and Implications for Genetic Testing. The Journal of Clinical Endocrinology & Metabolism 99: E183–E188. PubMed ID: 24170103
  • Stratakis CA, Horvath A. 2012. Carney Complex. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 20301463
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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