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Left Ventricular Noncompaction (LVNC) Sequencing Panel

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

Sequencing

Test Code Test Copy GenesCPT Code Copy CPT Codes
1333 ACTC1 81405 Add to Order
DTNA 81479
LDB3 81406
LMNA 81406
MYBPC3 81407
MYH7 81407
TAZ 81406
TNNT2 81406
VCL 81479
Full Panel Price* $1490.00
Test Code Test Copy Genes Total Price CPT Codes Copy CPT Codes
1333 Genes x (9) $1490.00 81405, 81406(x4), 81407(x2), 81479(x2) 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

Up to 20-30% of adults with LVNC are expected to have a pathogenic mutation in one of the genes in this panel (Ichida et al 2001; Vatta et al. 2003; Hermida-Prieto et al. 2004; Klaassen et al. 2008; Hoedemaekers et al. 2010).

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 ACTC1$690.00 81479 Add to Order
DTNA$690.00 81479
LDB3$690.00 81479
LMNA$690.00 81479
MYBPC3$690.00 81479
MYH7$690.00 81479
TAZ$690.00 81479
TNNT2$690.00 81479
VCL$690.00 81479
Full Panel Price* $840.00
Test Code Test Copy Genes Total Price CPT Codes Copy CPT Codes
600 Genes x (9) $840.00 81479(x9) 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

Very few gross deletions, duplications and complex rearrangements have been reported in patients with LVNC. Gross deletions and/or complex rearrangements have been reported in LMNA, MYBPC3, MYH7 and TAZ.

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Clinical Features

Left Ventricular Noncompaction (LVNC) cardiomyopathy is a heart condition believed to result from an arrest in cardiac development during embryogenesis, resulting in a spongy, noncompacted appearance. The numerous trabeculations are most pronounced in the left ventricle (Chin et al. 1990). Diagnosis is based on structural features using echocardiography and cardiac MRI. LVNC can occur in isolation or be found with other heart defects (most commonly dilated cardiomyopathy, hypertrophic cardiomyopathy, and/or congenital heart defects), genetic syndromes (such as Barth syndrome), and neuromuscular disorders (Pignatelli et al. 2003; Wald et al 2004; Oechslin et al. 2011; Jefferies 2013). Prevalence of LVNC is estimated to be ~0.25% of adults referred for echocardiography (Sandhu et al. 2008). Eighteen to fifty percent of isolated LVNC cases in adults are believed to be familial (Hoedemaekers et al. 2010).

Genetics

LVNC is a genetically heterogeneous disorder that is inherited in an autosomal dominant (ACTC1, DTNA, LDB3, LMNA, MYBPC3, MYH7, TNNT2, VCL) or X-linked recessive (TAZ) manner (Ichida et al 2001; Vatta et al. 2003; Hermida-Prieto et al. 2004; Klaassen et al. 2008; Hoedemaekers et al. 2010). Mutations in TAZ causes Barth syndrome, which can have LVNC as one of the symptoms. See individual gene test descriptions for information on molecular biology of gene products.

Testing Strategy

For this NextGen panel, we sequence all coding exons of the genes listed below, plus ~20 nucleotides of flanking DNA for each exon. 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 pathogenic and undocumented variants are confirmed by 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

Individuals with LVNC.

Genes

Official Gene Symbol OMIM ID
ACTC1 102540
DTNA 601239
LDB3 605906
LMNA 150330
MYBPC3 600958
MYH7 160760
TAZ 300394
TNNT2 191045
VCL 193065
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

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Congenital Muscular Dystrophy Sequencing Panel
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Distal Hereditary Myopathy Sequencing Panel
Hutchinson-Gilford Progeria Syndrome (HGPS) via the LMNA 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 TNNT2 Gene
Hypertrophic Cardiomyopathy Sequencing Panel
Hypertrophic Cardiomyopathy via the MYBPC3 Gene
Laminopathies via the LMNA Gene
Left Ventricular Noncompaction (LVNC) via the DTNA Gene
Limb-Girdle Muscular Dystrophy (LGMD) Sequencing Panel
Metabolic Myopathies, Rhabdomyolysis and Exercise Intolerance Sequencing Panel
Myofibrillar Myopathy Sequencing Panel
Myofibrillar Myopathy via the LDB3 (ZASP) Gene
Pan Cardiomyopathy Sequencing Panel
Sudden Cardiac Arrest Sequencing Panel

CONTACTS

Genetic Counselors
Geneticist
Citations
  • Chin TK, Perloff JK, Williams RG, Jue K, Mohrmann R. 1990. Isolated noncompaction of left ventricular myocardium. A study of eight cases. Circulation 82: 507–513. PubMed ID: 2372897
  • Hermida-Prieto et al. (2004) Familial dilated cardiomyopathy and isolated left ventricular noncompaction associated with lamin A/C gene mutations. Am J Cardiol. 94:50-4 PubMed ID: 15219508
  • Hoedemaekers et al. 2010. The Importance of Genetic Counseling, DNA Diagnostics, and Cardiologic Family Screening in Left Ventricular Noncompaction Cardiomyopathy. Circulation: Cardiovascular Genetics 3: 232–239. PubMed ID: 20530761
  • Ichida et al. (2001) Novel gene mutations in patients with left ventricular noncompaction or Barth syndrome. Circulation. 103:1256-63 PubMed ID: 11238270
  • Jefferies JL. 2013. Barth syndrome. American Journal of Medical Genetics Part C: Seminars in Medical Genetics 163: 198–205. PubMed ID: 23843353
  • Klaassen et al. (2008) Mutations in sarcomere protein genes in left ventricular noncompaction. Circulation. 117:2893-901 PubMed ID: 18506004
  • Oechslin E, Jenni R. 2011. Left ventricular non-compaction revisited: a distinct phenotype with genetic heterogeneity? European Heart Journal 32: 1446–1456. PubMed ID: 21285074
  • Pignatelli et al.  2003. Clinical Characterization of Left Ventricular Noncompaction in Children: A Relatively Common Form of Cardiomyopathy. Circulation 108: 2672–2678. PubMed ID: 14623814
  • Sandhu et al. 2008. Prevalence and characteristics of left ventricular noncompaction in a community hospital cohort of patients with systolic dysfunction. Echocardiography 25:8-10. PubMed ID: 18186774
  • Vatta et al. (2003) Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction. J Am Coll Cardiol. 42:2014-27 PubMed ID: 14662268
  • Wald et al. 2004. Determinants of outcome in isolated ventricular noncompaction in childhood. Am J Cardiol 94:1581-4 PubMed ID: 15589025
Order Kits
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
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.

Sequencing: 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 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.

Copy Number Variant Analysis: The PGxome test detects most 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 >95%, but may vary from gene-to-gene based on exon size, depth of coverage, and characteristics of the region.

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.

The sensitivity of this test is dependent on DNA quality.

General: 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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