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Hypertrophic Cardiomyopathy and Dilated Cardiomyopathy via the CSRP3 Gene

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

Sequencing

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
196 CSRP3$540.00 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
This test allows the detection of mutations in rare cases of patients with HCM and DCM (Hershberger et al. Circ Heart Fail 2:253-261, 2009).

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 CSRP3$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 Features
Hypertrophic cardiomyopathy (HCM) is a disease of the cardiac muscle characterized by idiopathic hypertrophy of the left ventricle without predisposing conditions, such as aortic stenosis or hypertension (Cirino et al. GeneReviews).  Hypertrophy of the right ventricle may also occur occasionally (Fifer and Vlahakes. Circulation 117:429-439, 2008). HCM is distinguished by extensive clinical variability with regards to the age of onset, pattern and extent of hypertrophy, and prognosis, even within individuals of the same family. Symptoms include dyspnea, exercise intolerance, chest pain, palpitations, arrhythmia, atrial fibrillation, presyncope, syncope and sudden death (Maron et al. N Engl J Med 316:780-789, 1987). Additional features include left ventricular outflow tract obstruction, which is associated with increased risk for heart failure and cardiovascular death if left untreated (Ommen et al. J Am Coll Cardiol 46:470-476, 2005; Agarwal et al. Am Coll Cardiol 55:823-834, 2010).  HCM is most often diagnosed with 2D echocardiography, but can also be diagnosed by the presence of myocyte disarray upon histological examination and through genetic testing.  HCM affects 1 in 500 people worldwide (Maron et al. Circulation 92:785-789, 1995).

Idiopathic Dilated cardiomyopathy (DCM) is a heterogeneous disease of the cardiac muscle. It is characterized by enlargement of the left  ventricle, systolic dysfunction, and diminished myocardial contractility (Hershberger et al. GeneReviews). Symptoms include arrhythmia, dyspnea, chest pain, palpitation, fainting, and congestive heart failure (Ikram et al. Br Heart J 57:521-527, 1987). Sudden death occurs in ~30% of patients with DCM (Tamburro and Wilber Am Heart J 124:1035-1045, 1992). 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 abnormalities has been documented.  Familial DCM is diagnosed based on family history and genetic testing.  The prevalence of DCM has been estimated at ~1 in 2700 individuals (Codd et al. Circulation 80:564-572, 1989).
Genetics
Familial HCM is inherited in an autosomal dominant manner caused by mutations in genes that encode different components of the sarcomere. Defects in fourteen genes, including CSRP3 (Chiu et al. J Am Coll Cardiol 55:1127-, 2010), account for approximately 60% of all HCM cases.  Most documented causative mutations in CSRP3 in patients with HCM are missense mutations, however frameshift mutations have also been reported (Geier and Perrot Circulation 107:1390-1395, 2003; Bos et al. Mol Genet Metab 88:78-85, 2006). In addition to HCM, CSRP3 mutations have been implicated in dilated cardiomyopathy (DCM).  CSRP3 associated DCM is inherited in an autosomal dominant manner.  All documented causative mutations in CSRP3 in patients with DCM are missense mutations (Mohapatra et al. Mol Genet Metab 80: 207-15, 2003; Hershberger et al. Clin Transl Sci 1:21-26, 2008).
Testing Strategy
The CSRP3 gene encodes the muscle LIM protein (MLP), a cardiac Z disc protein. This test involves bidirectional Sanger DNA sequencing of all 5 coding exons and splice sites of the CSRP3 gene. The full coding sequence of each exon plus ~20 bp of flanking DNA on either side are sequenced.  We will also sequence and single exon (Test #100) in family members of patients with a known mutation or to confirm research results.
Indications for Test
Patients with symptoms suggestive of HCM or DCM.

Gene

Official Gene Symbol OMIM ID
CSRP3 600824
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
Dilated Cardiomyopathy via the LAMA4 Gene

CONTACTS

Genetic Counselors
Geneticist
Citations
  • Agarwal S, et al. (2010) "Updated meta-analysis of septal alcohol ablation versus myectomy for hypertrophic cardiomyopathy." J Am Coll Cardiol 55:823-834. PubMed ID: 20170823
  • Bos, J. M., et.al. (2006). "Genotype-phenotype relationships involving hypertrophic cardiomyopathy-associated mutations in titin, muscle LIM protein, and telethonin." Mol Genet Metab 88(1): 78-85. PubMed ID: 16352453
  • Chiu, C., et.al. (2010). "Mutations in Alpha-Actinin-2 Cause Hypertrophic Cardiomyopathy A Genome-Wide Analysis." J Am Coll Cardiol. 55(11):1127-1135. PubMed ID: 20022194
  • Cirino, A.L., Ho, C. (2009). "Familial Hypertrophic Cardiomyopathy Overview." PubMed ID: 20301725
  • Codd MB. et al. 1989. Circulation. 80: 564-72. PubMed ID: 2766509
  • Fifer MA, Vlahakes GJ. 2008. Management of symptoms in hypertrophic cardiomyopathy. Circulation 117: 429-439. PubMed ID: 18212300
  • Geier, C., et.al. (2003). "Mutations in the human muscle LIM protein gene in families with hypertrophic cardiomyopathy." Circulation 107(10): 1390-5. PubMed ID: 12642359
  • Hershberger RE, Cowan J, Morales A, Siegfried JD. 2009. Progress with genetic cardiomyopathies: screening, counseling, and testing in dilated, hypertrophic, and arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circ. Heart Fail. 2: 253-261. PubMed ID: 19808347
  • Hershberger, R. et al. (2008) "Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP from 313 patients with familial or idiopathic dilated cardiomyopathy." Clin Transl Sci. 1:21-26. PubMed ID: 19412328
  • Hershberger, R. et.al. (2009). "Dilated Cardiomyopathy Overview." PubMed ID: 20301486
  • Ikram H. et al. 1987. British heart journal. 57: 521-7. PubMed ID: 3620228
  • Maron BJ, Bonow RO, Cannon RO 3rd, Leon MB, Epstein SE. 1987. Hypertrophic cardiomyopathy. Interrelations of clinical manifestations, pathophysiology, and therapy (1). N. Engl. J. Med. 316: 780-789. PubMed ID: 3547130
  • Maron, B. J., et.al. (1995). "Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary Artery Risk Development in (Young) Adults." Circulation 92(4): 785-9. PubMed ID: 7641357
  • Mohapatra, B., et.al. (2003). "Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis." Mol Genet Metab 80(1-2): 207-15. PubMed ID: 14567970
  • Ommen SR, Maron BJ, Olivotto I, Maron MS, Cecchi F, Betocchi S, Gersh BJ, Ackerman MJ, McCully RB, Dearani JA, Schaff HV, Danielson GK, Tajik AJ, Nishimura RA. 2005. Long-term effects of surgical septal myectomy on survival in patients with obstructive hypertrophic cardiomyopathy. J. Am. Coll. Cardiol. 46: 470-476. PubMed ID: 16053960
  • Tamburro P., Wilber D. 1992. American heart journal. 124: 1035-45. PubMed ID: 1529877
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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