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Dilated Cardiomyopathy Sequencing Panel with CNV Detection

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

Sequencing

Test Code Test Copy GenesCPT Code Copy CPT Codes
1339 ABCC9 81479, 81479 Add to Order
ACTC1 81405, 81479
ACTN2 81479, 81479
ANKRD1 81405, 81479
BAG3 81479, 81479
CAV3 81404, 81479
CRYAB 81479, 81479
CSRP3 81479, 81479
DES 81405, 81479
DMD 81408, 81161
DSC2 81406, 81479
DSG2 81406, 81479
DSP 81406, 81479
EMD 81405, 81404
EYA4 81479, 81479
FHL2 81479, 81479
FKTN 81405, 81479
GATAD1 81479, 81479
ILK 81479, 81479
LAMA4 81479, 81479
LAMP2 81405, 81479
LDB3 81406, 81479
LMNA 81406, 81479
MYBPC3 81407, 81479
MYH6 81407, 81479
MYH7 81407, 81479
MYPN 81479, 81479
NEXN 81479, 81479
NKX2-5 81479, 81479
PDLIM3 81479, 81479
PKP2 81406, 81479
PLN 81403, 81479
PRDM16 81479, 81479
RAF1 81406, 81479
RBM20 81479, 81479
SCN5A 81407, 81479
SGCD 81405, 81479
TAZ 81406, 81479
TCAP 81479, 81479
TMPO 81479, 81479
TNNC1 81405, 81479
TNNI3 81405, 81479
TNNT2 81406, 81479
TPM1 81405, 81479
TTN 81479, 81479
TTR 81404, 81479
VCL 81479, 81479
Full Panel Price* $1890.00
Test Code Test Copy Genes Total Price CPT Codes Copy CPT Codes
1339 Genes x (47) $1890.00 81161, 81403, 81404(x3), 81405(x10), 81406(x9), 81407(x4), 81408, 81479(x65) Add to Order
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).

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).

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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 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 ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads 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.

Diseases

Name Inheritance OMIM ID
3-Methylglutaconic Aciduria Type 2 XL 302060
Amyloidogenic Transthyretin Amyloidosis AD 105210
Arrhythmogenic Right Ventricular Cardiomyopathy, Type 10 AD 610193
Arrhythmogenic Right Ventricular Cardiomyopathy, Type 11 AD,AR 610476
Arrhythmogenic Right Ventricular Cardiomyopathy, Type 8 AD 607450
Arrhythmogenic Right Ventricular Cardiomyopathy, Type 9 AD 609040
Atrial Fibrillation, Familial, 10 AD 614022
Atrial Fibrillation, Familial, 12 AD 614050
Atrial Septal Defect 5 AD 612794
Atrial Septal Defect With Atrioventricular Conduction Defects AD 108900
Brugada Syndrome 1 AD 601144
Cardiomyopathy Dilated With Woolly Hair And Keratoderma AR 605676
Cardiomyopathy, Dilated, 1Hh AD 613881
Cardiomyopathy, dilated, 1II AD 615184
Cardiomyopathy, dilated, 1JJ AD 615235
Cardiomyopathy, Dilated, 1KK AD 615248
Cardiomyopathy, Dilated, 2B AR 614672
Cardiomyopathy, Dilated, 3B XL 302045
Danon Disease XL 300257
Dilated Cardiomyopathy 1A AD 115200
Dilated Cardiomyopathy 1Aa AD 612158
Dilated Cardiomyopathy 1C AD 601493
Dilated Cardiomyopathy 1CC AD 613122
Dilated Cardiomyopathy 1DD AD 613172
Dilated Cardiomyopathy 1I AD 604765
Dilated Cardiomyopathy 1J AD 605362
Dilated Cardiomyopathy 1L AD 606685
Dilated Cardiomyopathy 1N AD 607487
Dilated Cardiomyopathy 1R AD 613424
Dilated Cardiomyopathy 1S AD 613426
Dilated Cardiomyopathy 1X AR 611615
Dilated Cardiomyopathy 1Y AD 611878
Dilated Cardiomyopathy 2A AR 611880
Emery-Dreifuss Muscular Dystrophy 1, X-Linked XL 310300
Fallot Tetralogy AD 187500
Familial Hypertrophic Cardiomyopathy 1 AD 192600
Familial Hypertrophic Cardiomyopathy 12 AD 612124
Familial Hypertrophic Cardiomyopathy 13 AD 613243
Familial Hypertrophic Cardiomyopathy 14 AD 613251
Familial Hypertrophic Cardiomyopathy 15 AD 613255
Familial Hypertrophic Cardiomyopathy 18 AD 613874
Familial Hypertrophic Cardiomyopathy 2 AD 115195
Familial Hypertrophic Cardiomyopathy 3 AD 115196
Familial Hypertrophic Cardiomyopathy 4 AD 115197
Familial Hypertrophic Cardiomyopathy 7 AD 613690
Familial Hypertrophic Cardiomyopathy 9 AD 613765
Left ventricular noncompaction 10 AD 615396
Left Ventricular Noncompaction 8 AD 615373
Limb-Girdle Muscular Dystrophy, Type 2G AR 601954
Muscular Dystrophy-Dystroglycanopathy (Limb-Girdle), Type C, 5 AR 607155
Noonan Syndrome 5 AD 611553
Ventricular Septal Defect 3 AD 614432

Related Tests

Name
FHL1-Myopathies via the FHL1 Gene
RAF1-Related Disorders via the RAF1 Gene
Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia and DSP-Related Disorders via the DSP Gene
Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia Sequencing Panel
Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia via the DSC2 Gene
Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia via the DSG2 Gene
Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia via the PKP2 Gene
Autism Spectrum Disorders and Intellectual Disability (ASD-ID) Comprehensive Sequencing Panel with CNV Detection
Autosomal Dominant Limb Girdle Muscular Dystrophy (LGMD) Sequencing Panel
Autosomal Recessive Limb Girdle Muscular Dystrophy (LGMD) Sequencing Panel
Barth Syndrome via the TAZ Gene
Brugada Syndrome 1 via the SCN5A Gene
Brugada Syndrome Sequencing Panel
Cantu Syndrome via the ABCC9 Gene
Catecholaminergic Polymorphic Ventricular Tachycardia Sequencing Panel
Caveolinopathy via the CAV3 Gene
Centronuclear Myopathy Sequencing Panel
Charcot Marie Tooth - Axonal Neuropathy Sequencing Panel
Charcot Marie Tooth - Comprehensive Sequencing Panel
Ciliopathy Sequencing Panel
Comprehensive Cardiac Arrhythmia Sequencing Panel
Comprehensive Cardiology Sequencing Panel with CNV Detection
Comprehensive Neuromuscular Sequencing Panel
Comprehensive Neuropathy Sequencing Panel
Congenital Cataracts Sequencing Panel
Congenital Fiber Type Disproportion Sequencing Panel
Congenital Hypothyroidism and Thyroid Hormone Resistance Sequencing Panel
Congenital Muscular Dystrophy Sequencing Panel
Congenital Myopathy Sequencing Panel
Core Myopathy Sequencing Panel
Danon Disease/Glycogen Storage Disease IIb via the LAMP2 Gene
Deafness, Autosomal Dominant 10 (DFNA10) via the EYA4 Gene
Dilated Cardiomyopathy and Limb-Girdle Muscular Dystrophy Type 2F via the SGCD Gene
Dilated Cardiomyopathy via LAMA4 Gene Sequencing with CNV Detection
Dilated Cardiomyopathy via RBM20 Gene Sequencing with CNV Detection
Dilated Cardiomyopathy via the ANKRD1 Gene
Dilated Cardiomyopathy via NEXN Gene Sequencing with CNV Detection
Disorders of Fatty Acid Oxidation Sequencing Panel
Distal Hereditary Myopathy Sequencing Panel
Dystroglycan-Related Congenital Muscular Dystrophy Sequencing Panel
Dystroglycanopathy via the FKTN Gene
Dystrophinopathy via the DMD Gene
Dystrophinopathy via the DMD Gene
Emery-Dreifuss Muscular Dystrophy (EDMD1) via the EMD Gene
Epidermolysis Bullosa and Related Disorders Sequencing Panel with CNV Detection
Familial Amyloidosis via the TTR Gene
Familial Atrial Fibrillation Syndrome Sequencing Panel
Fetal Concerns Sequencing Panel with CNV Detection
Fukuyama Congenital Muscular Dystrophy via the FKTN Japanese Founder Mutation
Glycogen Storage Disease and Disorders of Glucose Metabolism Sequencing Panel
Heterotaxy and Conotruncal Heart Defects via the GDF1 Gene
Heterotaxy, Situs Inversus and Kartagener's Syndrome Sequencing Panel
Hutchinson-Gilford Progeria Syndrome (HGPS) via the LMNA Gene
Hypertrophic Cardiomyopathy and Dilated Cardiomyopathy via the ACTN2 Gene
Hypertrophic Cardiomyopathy and Dilated Cardiomyopathy via the CSRP3 Gene
Hypertrophic Cardiomyopathy and Dilated Cardiomyopathy via the MYH6 Gene
Hypertrophic Cardiomyopathy and Dilated Cardiomyopathy via the PLN Gene
Hypertrophic Cardiomyopathy and Dilated Cardiomyopathy via the TPM1 Gene
Hypertrophic Cardiomyopathy and Dilated Cardiomyopathy via the VCL Gene
Hypertrophic Cardiomyopathy and other MYH7-Related Disorders via the MYH7 Gene
Hypertrophic Cardiomyopathy and Related Disorders via the ACTC1 Gene
Hypertrophic Cardiomyopathy and Related Disorders via the TNNI3 Gene
Hypertrophic Cardiomyopathy and Related Disorders via the TNNT2 Gene
Hypertrophic Cardiomyopathy Sequencing Panel with CNV Detection
Hypertrophic Cardiomyopathy via the MYBPC3 Gene
Hypertrophic Cardiomyopathy via the TNNC1 Gene
Isolated Nonsyndromic Congenital Heart Defects via the NKX2-5 Gene
Isolated Nonsyndromic Congenital Heart Defects via the ZFPM2 (FOG2) Gene
Laminopathies via the LMNA Gene
Left Ventricular Noncompaction (LVNC) Sequencing Panel with CNV Detection
Limb Girdle Muscular Dystrophy Type 2I via the FKRP Gene
Limb Girdle Muscular Dystrophy, Type 2J and Tibial Muscular Dystrophy via the TTN Gene (exons 307 - 312)
Limb-Girdle Muscular Dystrophy (LGMD) Sequencing Panel
Long QT Syndrome Sequencing Panel
Metabolic Myopathies, Rhabdomyolysis and Exercise Intolerance Sequencing Panel
Myofibrillar Myopathy Sequencing Panel
Myofibrillar Myopathy via the CRYAB Gene
Myofibrillar Myopathy via the DES Gene
Myofibrillar Myopathy via the LDB3 (ZASP) Gene
Myofibrillar Myopathy, Childhood Onset via the BAG3 Gene
Nonsyndromic Hearing Loss and Deafness Sequencing Panel
Noonan Spectrum Disorders/Rasopathies Sequencing Panel
Pan Cardiomyopathy Sequencing Panel with CNV Detection
Premature Ovarian Failure (POF) Sequencing Panel with CNV Detection
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Telethoninopathy via the TCAP Gene
X-Linked Intellectual Disability Sequencing Panel with CNV Detection

CONTACTS

Genetic Counselors
Geneticist
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 with CNV Detection

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 on the NovaSeq 6000 using 2x150 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 NovaSeq 6000 is converted to fastqs by Illumina Bcl2Fastq, 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.

Copy number variants (CNVs) are also detected from NGS data. We utilize a CNV calling algorithm that compares mean read depth and distribution for each target in the test sample against multiple matched controls. Neighboring target read depth and distribution and zygosity of any variants within each target region are used to reinforce CNV calls. All CNVs are confirmed using another technology such as aCGH, MLPA, or PCR before they are reported.

Analytical Validity

Copy Number Variant Analysis: The PGxome test detects most larger deletions and duplications including intragenic CNVs and large cytogenetic events; however aberrations in a small percentage of regions may not be accurately detected due to sequence paralogy (e.g., pseudogenes, segmental duplications), sequence properties, deletion/duplication size (e.g., 1-3 exons vs. 4 or more exons), and inadequate coverage. In general, sensitivity for single, double, or triple exon CNVs is ~70% and for CNVs of four exon size or larger is close to 100%, but may vary from gene-to-gene based on exon size, depth of coverage, and characteristics of the region.

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.

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 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.

Balanced translocations or inversions are only rarely detected.

Certain types of sex chromosome aneuploidy may not be detected.  

In nearly all cases, our ability to determine the exact copy number change within a targeted region is limited.

Our ability to detect CNVs due to somatic mosaicism is limited.

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.

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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