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Atrial Fibrillation Syndrome via the KCNE5 Gene

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

Sequencing

Test Code TestIndividual Gene PriceCPT Code Copy CPT Codes
3971 KCNE5$990.00 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 28 days.

Clinical Sensitivity

Clinical sensitivity is not available because only a limited number of patients have been reported. Most reported pathogenic variants in KCNE5 are missense or nonsense. No large deletions or duplications have been reported.

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Clinical Features

Atrial fibrillation is a disorder with an abnormal and often rapid heart rhythm. This condition is characterized by uncoordinated electrical activity in the atria, “irregularly irregular” pattern in ECG and supraventricular tachyarrhythmia, which deteriorates atrial mechanical function. If untreated, atrial fibrillation can lead to a reduction in cardiac output, atrial thrombus formation and increased risk for mortality. Patients with atrial fibrillation can present dizziness, chest pain, palpitations, shortness of breath, or even syncope (Fuster et al. 2011). Complications of atrial fibrillation can occur at any age and some people may never experience any health problems. The likelihood of developing arrhythmias increases with age. Atrial fibrillation can be prevented and treated (Van Wagoner et al. 2015).

Genetics

Atrial fibrillation (AF) is the most common cardiac arrhythmia disorder, and currently affects nearly 3 million Americans (Naccarelli et al. 2009). Although the incidence of the familial form of atrial fibrillation is unknown, having a family member with AF increases the risk for the disorder by 40% (Lubitz et al. 2010).

Familial atrial fibrillation is highly heterogeneous and transmitted in an autosomal dominant pattern, with the exception of KCNE5. There are at least 15 genes associated with familial atrial fibrillation: ABCC9, GJA5, KCNA5, KCND3, KCNE1, KCNE2, KCNE5, KCNH2, KCNJ2, KCNQ1, NPPA, SCN1B, SCN2B, SCN3B and SCN5A. The majority of genes associated with atrial fibrillation are components of two important ion channels: potassium and sodium. Both loss and gain of function variants can affect the current of the ion channels and change the atrial action potential and refraction period (Tucker et al. 2014). 

Pathogenic variants in KCNE5 cause atrial fibrillation and other arrhythmia disorders and are inherited in an X-linked dominant manner. Both affected males and females have been reported with a pathogenic variant in KCNE5 (Ravn et al 2008; Ohno et al. 2011). KCNE5 (also known as KCNE1L) encodes a member of the voltage-gated potassium channel. KCNE5 contains a single exon, encodes 142 amino acids and is located at Xq22.3 (Piccini et al. 1999). Genetic variants in KCNE5 affect the voltage-gated atrial-specific potassium current IK  and disturb the  balance of current responsible for the characteristics of repolarization of the atrial action potential via its interaction with Kv4.3 or other channels (Ravn et al. 2008).

Testing Strategy

For this NextGen test, the full coding regions plus ~20 bp of non-coding DNA flanking each exon are sequenced for the gene listed below. 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, likely pathogenic, or variants of uncertain significance are confirmed by Sanger sequencing.

Indications for Test

All patients with symptoms suggestive of familial atrial fibrillation are candidates for this test.

Gene

Official Gene Symbol OMIM ID
KCNE5 300328
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID

Related Tests

Name
Brugada Syndrome Sequencing Panel
Comprehensive Cardiac Arrhythmia Sequencing Panel
Familial Atrial Fibrillation Syndrome Sequencing Panel

CONTACTS

Genetic Counselors
Geneticist
Citations
  • Fuster V. et al. 2011. Circulation. 123: e269-367. PubMed ID: 21382897
  • Lubitz S.A. et al. 2010. Jama. 304: 2263-9. PubMed ID: 21076174
  • Naccarelli G.V. et al. 2009. The American Journal of Cardiology. 104: 1534-9. PubMed ID: 19932788
  • Ohno S. et al. 2011. Circulation. Arrhythmia and Electrophysiology. 4: 352-61. PubMed ID: 21493962
  • Piccini M. et al. 1999. Genomics. 60:251-7. PubMed ID: 10493825
  • Ravn L.S. et al. 2008. Heart Rhythm. 5: 427-35. PubMed ID: 18313602
  • Tucker N.R., Ellinor P.T. 2014. Circulation Research. 114: 1469-82. PubMed ID: 24763465
  • Van Wagoner D.R. et al. 2015. Heart Rhythm  12: e5-e29. PubMed ID: 25460864
Order Kits
TEST METHODS

NextGen Sequencing

Test Procedure

We use a combination of Next Generation Sequencing (NGS) and Sanger sequencing technologies to cover the full coding regions of the listed genes plus ~20 bases of non-coding DNA flanking each exon.  As required, genomic DNA is extracted from the patient specimen.  For NGS, patient DNA corresponding to these regions is captured using an optimized set of DNA hybridization probes.  Captured DNA is sequenced using Illumina’s Reversible Dye Terminator (RDT) platform (Illumina, San Diego, CA, USA).  Regions with insufficient coverage by NGS are covered by Sanger sequencing.  All pathogenic, likely pathogenic, or 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.

Patient DNA sequence is aligned to the genomic reference sequence for the indicated gene region(s). All differences from the reference sequences (sequence variants) are assigned to one of five interpretation categories, listed below, per ACMG Guidelines (Richards et al. 2015).

(1) Pathogenic Variants
(2) Likely Pathogenic Variants
(3) Variants of Uncertain Significance
(4) Likely Benign Variants
(5) Benign, Common Variants

Human Genome Variation Society (HGVS) recommendations are used to describe sequence variants (http://www.hgvs.org).  Rare variants and undocumented variants are nearly always classified as likely benign if there is no indication that they alter protein sequence or disrupt splicing.

Analytical Validity

As of March 2016, 6.36 Mb of sequence (83 genes, 1557 exons) generated in our lab was compared between Sanger and NextGen methodologies. We detected no differences between the two methods. The comparison involved 6400 total sequence variants (differences from the reference sequences). Of these, 6144 were nucleotide substitutions and 256 were insertions or deletions. About 65% of the variants were heterozygous and 35% homozygous. The insertions and deletions ranged in length from 1 to over 100 nucleotides.

In silico validation of insertions and deletions in 20 replicates of 5 genes was also performed. The validation included insertions and deletions of lengths between 1 and 100 nucleotides. Insertions tested in silico: 2200 between 1 and 5 nucleotides, 625 between 6 and 10 nucleotides, 29 between 11 and 20 nucleotides, 25 between 21 and 49 nucleotides, and 23 at or greater than 50 nucleotides, with the largest at 98 nucleotides. All insertions were detected. Deletions tested in silico: 1813 between 1 and 5 nucleotides, 97 between 6 and 10 nucleotides, 32 between 11 and 20 nucleotides, 20 between 21 and 49 nucleotides, and 39 at or greater than 50 nucleotides, with the largest at 96 nucleotides. All deletions less than 50 nucleotides in length were detected, 13 greater than 50 nucleotides in length were missed. Our standard NextGen sequence variant calling algorithms are generally not capable of detecting insertions (duplications) or heterozygous deletions greater than 100 nucleotides. Large homozygous deletions appear to be detectable.   

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 Sanger sequencing does not reveal any difference from the reference sequence, or when a sequence variant is homozygous, we cannot be certain that we were able to detect both patient alleles.  Occasionally, a patient may carry an allele which does not 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 Sequencing tests are generally not capable of detecting Copy Number Variants (CNVs).

We sequence all coding exons for each given transcript, plus ~20 bp of flanking non-coding DNA for each exon.  Test reports contain no information about other portions of the gene, such as regulatory domains, deep intronic regions or any currently uncharacterized alternative exons.

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 PCR.

Unless otherwise indicated, DNA sequence data is obtained from a specific cell-type (usually leukocytes 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.

Rare, low probability interpretations of sequencing results, such as for example the occurrence of de novo mutations in recessive disorders, are generally not included in the reports.

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.

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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
  • The first four pages of the requisition form must accompany all specimens.
  • Billing information is on the third and fourth pages.
  • Specimen and shipping instructions are listed on the fifth and sixth pages.
  • All testing must be ordered by a qualified healthcare provider.

SPECIMEN TYPES
WHOLE BLOOD

(Delivery accepted Monday - Saturday)

  • Collect 3-5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10-20 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 good for up to 48 hours.
  • If refrigerated, blood specimen is good for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.

DNA

(Delivery accepted Monday - Saturday)

  • NextGen Sequencing Tests: Send in screw cap tube at least 10 µg of purified DNA at a concentration of at least 50 µg/ml
  • Sanger Sequencing Tests: Send in a screw cap tube at least 15 µg of purified DNA at a concentration of at least 20 µg/ml. For tests involving the sequencing of more than three genes, send an additional 5 µg DNA per gene. DNA may be shipped at room temperature.
  • Deletion/Duplication via aCGH: Send in screw cap tube at least 1 µg of purified DNA at a concentration of at least 100 µg/ml.
  • Whole-Genome Chromosomal Microarray: Collect at least 5 µg of DNA in TE (10 mM Tris-cl pH 8.0, 1mM EDTA), dissolved in 200 µl at a concentration of at least 100 ng/ul (indicate concentration on tube label). DNA extracted using a column-based method (Qiagen) or bead-based technology is preferred.

CELL CULTURE

(Delivery accepted Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Ship at least two T25 flasks of confluent cells.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We do not culture cells.