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Dilated Cardiomyopathy Sequencing Panel
- Summary and Pricing
- Clinical Features and Genetics
- Citations
- Methods
- Ordering/Specimens
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TEST METHODS
Sequencing
| Test Code | Test Copy Genes | CPT Code Copy CPT Codes | |
|---|---|---|---|
| 1339 | ABCC9 | 81479 | Add |
| ACTC1 | 81405 | ||
| ACTN2 | 81479 | ||
| ANKRD1 | 81405 | ||
| BAG3 | 81479 | ||
| CAV3 | 81404 | ||
| CRYAB | 81479 | ||
| CSRP3 | 81479 | ||
| DES | 81405 | ||
| DMD | 81408 | ||
| DSC2 | 81406 | ||
| DSG2 | 81406 | ||
| DSP | 81406 | ||
| EMD | 81405 | ||
| EYA4 | 81479 | ||
| FHL2 | 81479 | ||
| FKTN | 81405 | ||
| GATAD1 | 81479 | ||
| ILK | 81479 | ||
| LAMA4 | 81479 | ||
| LAMP2 | 81405 | ||
| LDB3 | 81406 | ||
| LMNA | 81406 | ||
| MYBPC3 | 81407 | ||
| MYH6 | 81407 | ||
| MYH7 | 81407 | ||
| MYPN | 81479 | ||
| NEXN | 81479 | ||
| NKX2-5 | 81479 | ||
| PDLIM3 | 81479 | ||
| PKP2 | 81406 | ||
| PLN | 81403 | ||
| PRDM16 | 81479 | ||
| RAF1 | 81406 | ||
| RBM20 | 81479 | ||
| SCN5A | 81407 | ||
| SGCD | 81405 | ||
| TAZ | 81406 | ||
| TCAP | 81479 | ||
| TMPO | 81479 | ||
| TNNC1 | 81405 | ||
| TNNI3 | 81405 | ||
| TNNT2 | 81406 | ||
| TPM1 | 81405 | ||
| TTN | 81479 | ||
| TTR | 81404 | ||
| VCL | 81479 | ||
| Full Panel Price* | $1890.00 | ||
| Test Code | Test Copy Genes | Total Price | CPT Codes Copy CPT Codes | |
|---|---|---|---|---|
| 1339 | Genes x (47) |
$1890.00 | 81403, 81404(x2), 81405(x10), 81406(x9), 81407(x4), 81408, 81479(x20) | Add |
Pricing Comment
If you would like to order a subset of these genes contact us to discuss pricing.
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 28 days.
Clinical Sensitivity
This panel can detect pathogenic variants in 35-40% of patients with Familial Dilated Cardiomyopathy (Hershberger et al. 2013; McNally et al. 2013).
Deletion/Duplication Testing via aCGH
| Test Code | Test Copy Genes | Individual Gene Price | CPT Code Copy CPT Codes | |
|---|---|---|---|---|
| 600 | ABCC9 | $690.00 | 81479 | Add |
| ACTC1 | $690.00 | 81479 | ||
| ACTN2 | $690.00 | 81479 | ||
| BAG3 | $690.00 | 81479 | ||
| CAV3 | $690.00 | 81479 | ||
| CRYAB | $690.00 | 81479 | ||
| CSRP3 | $690.00 | 81479 | ||
| DES | $690.00 | 81479 | ||
| DMD | $690.00 | 81161 | ||
| DSC2 | $690.00 | 81479 | ||
| DSG2 | $690.00 | 81479 | ||
| DSP | $690.00 | 81479 | ||
| EMD | $690.00 | 81404 | ||
| EYA4 | $690.00 | 81479 | ||
| FKTN | $690.00 | 81479 | ||
| LAMP2 | $690.00 | 81479 | ||
| LDB3 | $690.00 | 81479 | ||
| LMNA | $690.00 | 81479 | ||
| MYBPC3 | $690.00 | 81479 | ||
| MYH6 | $690.00 | 81479 | ||
| MYH7 | $690.00 | 81479 | ||
| NKX2-5 | $690.00 | 81479 | ||
| PKP2 | $690.00 | 81479 | ||
| PLN | $690.00 | 81479 | ||
| RAF1 | $690.00 | 81479 | ||
| SCN5A | $690.00 | 81479 | ||
| SGCD | $690.00 | 81479 | ||
| TAZ | $690.00 | 81479 | ||
| TCAP | $690.00 | 81479 | ||
| TMPO | $690.00 | 81479 | ||
| TNNC1 | $690.00 | 81479 | ||
| TNNI3 | $690.00 | 81479 | ||
| TNNT2 | $690.00 | 81479 | ||
| TPM1 | $690.00 | 81479 | ||
| TTN | $690.00 | 81479 | ||
| TTR | $690.00 | 81479 | ||
| VCL | $690.00 | 81479 | ||
| Full Panel Price* | $1670.00 | |||
| Test Code | Test Copy Genes | Total Price | CPT Codes Copy CPT Codes | |
|---|---|---|---|---|
| 600 | Genes x (37) |
$1670.00 | 81161, 81404, 81479(x35) | Add |
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
Gross deletions or duplications not detectable by Sanger sequencing have been reported in CAV3, DES, DSP, NKX2-5, PKP2, and SCN5A as individual cases (Human Gene Mutation Database).
Clinical Features
Dilated cardiomyopathy (DCM) is a heterogeneous disease of the cardiac muscle. It is characterized by dilatation of the left, right, or both ventricles, systolic dysfunction, and diminished myocardial contractility. Symptoms include arrhythmia, dyspnea, chest pain, palpitation, fainting, and congestive heart failure (Ikram et al. 1987). Additional features may include conduction defects, woolly hair, and skeletal myopathy (Møller et al. 2009). Although symptoms of DCM usually begin in adulthood, an extensive clinical variability between individuals concerning the age of onset, penetrance, and extent of structural and functional abnormality has been documented. The prevalence of DCM has been estimated at ~1/2700 (Codd et al. 1989), but it could be 10-folder higher as proposed by another study (Hershberger et al. 2013). Up to 50% of DCM cases are classified as idiopathic and 30-50% of idiopathic DCM cases are inherited and termed Familial Dilated cardiomyopathy (FDCM) (Felker et al. 2000; de Gonzalo-Calvo et al. 2017). For additional information see GeneReviews (Hershberger and Morales 2013).
Genetics
DCM is genetically heterogeneous disease and most commonly inherited in an autosomal dominant manner. However, other modes of inheritance have been described, such as autosomal recessive (FKTN and GATAD1); X-linked recessive (DMD, EMD and TAZ), and X-linked dominant (LAMP2). The DCS2, DSP, LMNA, SCN5A, TCAP*, TNNI3 and TTN genes are associated with autosomal dominant and recessive disorders. (OMIM; Human Gene Mutation Database, *limited cases). See individual gene test descriptions for information on molecular biology of gene products.
Testing Strategy
For this Next Generation Sequencing (NGS) test, sequencing is accomplished by capturing specific regions with an optimized solution-based hybridization kit, followed by massively parallel sequencing of the captured DNA fragments. Additional Sanger sequencing is performed for any regions not captured or with insufficient number of sequence reads. All reported pathogenic, likely pathogenic, and variants of uncertain significance are confirmed by Sanger sequencing.
For Sanger sequencing, polymerase chain reaction (PCR) is used to amplify targeted regions. After purification of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit. PCR products are resolved by electrophoresis on an ABI 3730xl capillary sequencer. In nearly all cases, cycle sequencing is performed separately in both the forward and reverse directions.
This panel provides full coverage of all coding exons of the genes listed, plus ~20 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads for coding regions and 0-10 bases of flanking DNA, >10X NGS reads for 11-20 bases of flanking DNA, or Sanger sequencing.
Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).
Indications for Test
Patients with symptoms and medical history suggestive of Dilated cardiomyopathy.
Genes
| Official Gene Symbol | OMIM ID |
|---|---|
| ABCC9 | 601439 |
| ACTC1 | 102540 |
| ACTN2 | 102573 |
| ANKRD1 | 609599 |
| BAG3 | 603883 |
| CAV3 | 601253 |
| CRYAB | 123590 |
| CSRP3 | 600824 |
| DES | 125660 |
| DMD | 300377 |
| DSC2 | 125645 |
| DSG2 | 125671 |
| DSP | 125647 |
| EMD | 300384 |
| EYA4 | 603550 |
| FHL2 | 602633 |
| FKTN | 607440 |
| GATAD1 | 614518 |
| ILK | 602366 |
| LAMA4 | 600133 |
| LAMP2 | 309060 |
| LDB3 | 605906 |
| LMNA | 150330 |
| MYBPC3 | 600958 |
| MYH6 | 160710 |
| MYH7 | 160760 |
| MYPN | 608517 |
| NEXN | 613121 |
| NKX2-5 | 600584 |
| PDLIM3 | 605889 |
| PKP2 | 602861 |
| PLN | 172405 |
| PRDM16 | 605557 |
| RAF1 | 164760 |
| RBM20 | 613171 |
| SCN5A | 600163 |
| SGCD | 601411 |
| TAZ | 300394 |
| TCAP | 604488 |
| TMPO | 188380 |
| TNNC1 | 191040 |
| TNNI3 | 191044 |
| TNNT2 | 191045 |
| TPM1 | 191010 |
| TTN | 188840 |
| TTR | 176300 |
| VCL | 193065 |
| Inheritance | Abbreviation |
|---|---|
| Autosomal Dominant | AD |
| Autosomal Recessive | AR |
| X-Linked | XL |
| Mitochondrial | MT |
Diseases
Related Tests
CONTACTS
Genetic Counselors
- Genetic Counselor Team - clinicaldnatesting@preventiongenetics.com
Geneticist
- Guoli Sun, MD, PhD, FACMG - guoli.sun@preventiongenetics.com
Citations
- Codd M.B. et al. 1989. Circulation. 80: 564-72. PubMed ID: 2766509
- de Gonzalo-Calvo D. et al. 2017. International Journal of Cardiology. 228: 870-80. PubMed ID: 27889554
- Felker G.M. et al. 2000. The New England Journal of Medicine. 342: 1077-84. PubMed ID: 10760308
- Hershberger R.E., Morales A. 2013. Dilated Cardiomyopathy Overview. 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: 20301486
- Human Gene Mutation Database (Bio-base).
- Ikram H. et al. 1987. British heart journal. 57: 521-7. PubMed ID: 3620228
- Møller D.V. et al. 2009. European Journal of Human Genetics. 17: 1241-9. PubMed ID: 19293840
- McNally E.M. et al. 2013. The Journal of Clinical Investigation. 123: 19-26. PubMed ID: 23281406
- Online Mendelian Inheritance in Man: http://www.omim.org/
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TEST METHODS
Exome Sequencing
Test Procedure
For the PGxome we use Next Generation Sequencing (NGS) technologies to cover the coding regions of targeted genes plus ~10 bases of non-coding DNA flanking each exon. As required, genomic DNA is extracted from patient specimens. Patient DNA corresponding to these regions is captured using Agilent Clinical Research Exome hybridization probes. Captured DNA is sequenced using Illumina's Reversible Dye Terminator (RDT) platform NextSeq 500 using 150 by 100 bp paired end reads (Illumina, San Diego, CA, USA). The following quality control metrics are generally achieved: >97% of target bases are covered at >20x, and mean coverage of target bases >120x. Data analysis and interpretation is performed by the internally developed software Titanium-Exome. In brief, the output data from the NextSeq 500 is converted to fastqs by Illumina Bcl2Fastq 1.8.4, and mapped by BWA. Variant calls are made by the GATK Haplotype caller and annotated using in house software and SnpEff. Variants are filtered and annotated using VarSeq (www.goldenhelix.com). Common benign, likely benign, and low quality variants are filtered from analysis. All reported pathogenic, likely pathogenic, and variants of uncertain significance are confirmed by Sanger sequencing.
For Sanger sequencing, polymerase chain reaction (PCR) is used to amplify targeted regions. After purification of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit. PCR products are resolved by electrophoresis on an ABI 3730xl capillary sequencer. In nearly all cases, cycle sequencing is performed separately in both the forward and reverse directions.
Analytical Validity
Analytical Limitations
Interpretation of the test results is limited by the information that is currently available. Better interpretation should be possible in the future as more data and knowledge about human genetics and this specific disorder are accumulated.
When sequencing does not reveal any heterozygous differences from the reference sequence, we cannot be certain that we were able to detect both patient alleles. Occasionally, a patient may carry an allele which does not capture or amplify, due to a large deletion or insertion. In these cases, the report will contain no information about the second allele. Our Sanger and NGS tests (including PGxome) are generally not capable of detecting Copy Number Variants (CNVs).
For technical reasons, the PGxome test is not 100% sensitive. Some exons cannot be efficiently captured, and some genes cannot be accurately sequenced because of the presence of multiple copies in the genome. Therefore, a small fraction of sequence variants relevant to the patient's health will not be detected.
We sequence coding exons for most given transcripts, plus ~10 bp of flanking non-coding DNA for each exon. Unless specifically indicated, test reports contain no information about other portions of the gene, such as regulatory domains, deep intronic regions, uncharacterized alternative exons, chromosomal rearrangements, repeat expansions, epigenetic effects, and mitochondrial genome variants.
In most 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 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 amplification.
Unless otherwise indicated, DNA sequence data is obtained from a specific cell-type (usually leukocytes if taken from whole blood). Test reports contain no information about the DNA sequence in other cell-types.
We cannot be certain that the reference sequences are correct.
We have confidence in our ability to track a specimen once it has been received by PreventionGenetics. However, we take no responsibility for any specimen labeling errors that occur before the sample arrives at PreventionGenetics.
A negative finding does not rule out a genetic diagnosis.
Genetic counseling to help to explain test results to the patients and to discuss reproductive options is recommended.
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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