Forms

Long QT Syndrome and Jervell and Lange-Nielsen Syndrome via the KCNE1 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
1043 KCNE1$440.00 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
Pathogenic variants have been found in either KCNQ1 or KCNE1 in 94% of individuals with clinical JLNS undergoing molecular testing. The pathogenic variants may be located in all coding exons. Current experience indicates that 33% are compound heterozygotes (Schwartz et al 2006). About 90 percent of Jervell and Lange-Nielsen syndrome cases are caused by mutations in the KCNQ1 gene. KCNE1 mutations are responsible for the remaining 10 percent of cases (Schwartz et al. 2006; Tyson et al. 2000). Splawski et al (2000) screened 262 unrelated LQTS patients for causative variants in 5 genes: KVLQT1, HERG, SCN5A, KCNE1 and KCNE2. They reported causative variants in 68% of their subjects. Of these, 45% were in HERG, 42% in KVLQT1, 8% in SCN5A, 3% in KCNE1 and 2% in KCNE2.

See More

See Less

Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 KCNE1$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 Sensitivity
Gross deletions and duplications in the KCNE1 gene have not been reported in patients with Long QT syndrome and Jervell and Lange-Nielsen syndrome (Human Gene Mutation Database).

See More

See Less

Clinical Features
Long QT syndrome (LQTS) is a heritable channelopathy characterized by an exceedingly prolonged cardiac repolarization that may trigger ventricular arrhythmias (torsade de pointes), recurrent syncopes, seizure, or sudden cardiac death (SCD) (Cerrone et al. 2012). The incidence of LQTS has been estimated between 1 in 2500 and 1 in 7000 in the general population.  LQTS can manifest with syncope and cardiac arrest that is commonly triggered by adrenergic stress, often precipitated by emotion or exercise. Roughly 10% to 15% of patients experience symptoms at rest or during the night (Schwartz et al. 2001). The mean age of onset of symptoms is 12 years, and earlier onset usually is associated with a more severe form of the disease (Priori et al 2004). Inherited LQTS occurs due to mutations in multiple genes such as KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), ANK2(LQT4), KCNE1 (LQT5), KCNE2 (LQT6), KCNJ2(LQT7), CACNA1C(LQT8), CAV3(LQT9), SCN4B(LQT10), AKAP9(LQT11), SNTA1(LQT12) and KCNJ5 (LQT13), but it can also be acquired (acquired LQTS), usually as a result of pharmacological therapy. A small percentage of cases of LQTS occur in people who have an underlying variation in the KCNE1 gene.

Jervell and Lange-Nielsen Syndrome (JLNS) is characterized by congenital profound bilateral sensorineural hearing loss and long QTc, usually greater than 500 msec. If untreated, the irregular heartbeats can lead to life-threatening ventricular arrhythmias, and a high risk of sudden cardiac death (Schwartz et al. 2006). Jervell and Lange-Nielsen syndrome prevalence remains largely unknown due to the high mortality in infancy and lack of comprehensive neonatal screening methods. KCNQ1 or KCNE1 are the only two genes in which pathogenic variants are known to cause JLNS. JLNS is usually detected during early childhood and is inherited as an autosomal dominant genetic disorder. More than half of the untreated cases of JLNS result in death before the age of 15.
Genetics
Jervell and Lange-Nielsen Syndrome is inherited in an autosomal dominant pattern. About 90 percent of Jervell and Lange-Nielsen syndrome cases are caused by mutations in the KCNQ1 gene. KCNE1 mutations are responsible for the remaining 10 percent of cases (Schwartz et al. 2006; Tyson et al. 2000). The subtype of Jervell and Lange-Nielsen syndrome caused by mutations in the KCNQ1 gene is called JLNS1. Another  subtype,  JLNS2, is  caused by mutations in the KCNE1 gene, also known as Ward-Romano syndrome, and Long QT syndrome 5. So far, KCNE1 mutations found in JLNS are missense/nonsense (87%) and small deletion/insertion/indels (11%) (Human Gene Mutation Database).

KCNE1 (potassium voltage-gated channel, Isk-related family, member 1) belongs to the potassium channel KCNE gene family.  The KCNE1 gene regulates a potassium channel made up of proteins produced by the KCNQ1 gene. KCNE1 and KCNQ1 work together to form a potassium channel that transports positively charged potassium ions out of cells, which is critical for maintaining the normal functions of the inner ear and cardiac muscle (Crump et al. 2014).
Testing Strategy
This test involves bidirectional Sanger DNA sequencing of the single coding exon and splice sites of the KCNE1 gene. The full coding sequence of the exon plus ~ 20 bp of flanking DNA on either side are sequenced. We will also sequence any single portion (Test #100) of this exon in family members of patients with a known mutation or to confirm research results.
Indications for Test
All patients with symptoms suggestive of Long QT syndrome/ Jervell and Lange-Nielsen syndrome are candidates for this test.

Gene

Official Gene Symbol OMIM ID
KCNE1 176261
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Tests

Name
Long QT Syndrome and Jervell and Lange-Nielsen syndrome via the KCNQ1 Gene
Long QT Syndrome Sequencing Panel
Long QT Syndrome via the ANK2 Gene
Long QT Syndrome via the SCN4B Gene
Long QT Syndrome via the AKAP9 Gene
Short QT Syndrome Sequencing Panel

CONTACTS

Genetic Counselors
Geneticist
Citations
  • Cerrone M. et al. 2012. Circulation. Cardiovascular genetics. 5: 581-90. PubMed ID: 23074337
  • Crump SM, Abbott GW. 2014. Arrhythmogenic KCNE gene variants: current knowledge and future challenges. Front Genet 5: 3. PubMed ID: 24478792
  • Human Gene Mutation Database (Bio-base).
  • Priori SG. et al. 2004. JAMA. 292: 1341-4. PubMed ID: 15367556
  • Schwartz PJ, Spazzolini C, Crotti L, Bathen J, Amlie JP, Timothy K, Shkolnikova M, Berul CI, Bitner-Glindzicz M, Toivonen L, Horie M, Schulze-Bahr E, Denjoy I. 2006. The Jervell and Lange-Nielsen syndrome: natural history, molecular basis, and clinical outcome. Circulation 113: 783–790. PubMed ID: 16461811
  • Schwartz PJ. et al. 2001. Circulation. 103: 89-95. PubMed ID: 11136691
  • Splawski I. et al. 2000. Circulation. 102: 1178-85. PubMed ID: 10973849
  • Tyson J, Tranebjaerg L, McEntagart M, Larsen LA, Christiansen M, Whiteford ML, Bathen J, Aslaksen B, Sørland SJ, Lund O, Pembrey ME, Malcolm S, Bitner-Glindzicz M. 2000. Mutational spectrum in the cardioauditory syndrome of Jervell and Lange-Nielsen. Hum. Genet. 107: 499–503. PubMed ID: 11140949
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.
loading Loading... ×