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Dilated Cardiomyopathy via the ANKRD1 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
2253 ANKRD1$810.00 81405 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 ANKRD1 were identified in ~2% of Dilated Cardiomyopathy cases (Moulik et al. 2009; Duboscq-Bidot et al. 2009).

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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).

Genetics

Dilated Cardiomyopathy (DCM) is familial in 30%-50% of cases (de Gonzalo-Calvo et al. 2017). Pathogenic variants in ANKRD1 have been reported to be associated with Dilated Cardiomyopathy, and are inherited in an autosomal dominant pattern (limited cases) (Duboscq-Bidot et al. 2009; Moulik et al. 2009). Cardiac-specific stress-response protein (CARP) encoded by ANKRD1 belongs to the muscle ankyrin repeat protein (MARP) family. CARP interacts with N2A domain of titin and translocates into nucleus to regulate the transcription in response to a stretch as part of mechanical stretch-based signaling machinery in cardiac myocytes. Pathogenic variants in ANKRD1 alter the interaction between CARP and associated protein and impair the stretch based cellular pathway. CARP is up regulated in dilated cardiomyopathy in response to mechanical stress (Bogomolovas et al. 2015) The ANKRD1 gene contains 9 coding exons, encodes 319 amino acids and is located at 10q23.31. Most reported pathogenic variants in ANKRD1 are missense or nonsense (Human Gene Mutation Database).

Testing Strategy

This test involves bidirectional DNA sequencing of all 9 coding exons and splice sites of the ANKRD1 gene. The full coding sequence of each exon plus ~20 bp of flanking DNA on either side are sequenced. We will also sequence any single exon (Test #100) in family members of patients with a known pathogenic variant or to confirm research results.

Indications for Test

Patients with Dilated Cardiomyopathy.

Gene

Official Gene Symbol OMIM ID
ANKRD1 609599
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID

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CONTACTS

Genetic Counselors
Geneticist
Citations
  • Bogomolovas J. et al. 2015. Biomed Research International. 2015: 273936. PubMed ID: 25961010
  • 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
  • Duboscq-Bidot L. et al. 2009. European Heart Journal. 30: 2128-36. PubMed ID: 19525294
  • 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
  • Moulik M. et al. 2009. Journal of the American College of Cardiology. 54: 325-33. PubMed ID: 19608030
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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.

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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