• Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit




Associated disorders

The KCNJ2 gene is associated with autosomal dominant Andersen-Tawil syndrome, also known as long QT syndrome (LQTS), type 7 (MedGen UID: 327586), short QT syndrome (SQTS) (MedGen UID: 400662), and catecholaminergic polymorphic ventricular tachycardia (CPVT) (PMID: 22589293). Additionally, the KCNJ2 gene has preliminary evidence supporting a correlation with autosomal dominant atrial fibrillation (MedGen UID: 462781).

Pathogenic KCNJ2 variants are associated with ~60% of clinical cases of Andersen-Tawil syndrome, a subtype of LQTS. Overall, KCNJ2 is associated with an unknown percentage of clinical cases of LQTS. KCNJ2 is also a rare cause of SQTS and causes an unknown percentage of CPVT and atrial fibrillation cases.

The KCNJ2 gene encodes the potassium inwardly-rectifying channel, subfamily J, member 2. The electrical activity of muscle is controlled by the movement of potassium, sodium and calcium ions across the cardiac muscle cells. Mutations in genes that encode potassium channels or subunits are a common cause of inherited cardiac arrhythmias.

  1. Smith, AH, et al. Andersen-Tawil syndrome. Indian Pacing Electrophysiol J. 2006; 6(1):32-43. doi: 10.1016/j.hrthm.2006.08.015. PMID: 16943893
  2. Statland, JM, et al. Andersen-Tawil Syndrome. 2004 Nov 22. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1264/ PMID: 20301441
  3. Lieve, KV, et al. Results of genetic testing in 855 consecutive unrelated patients referred for long QT syndrome in a clinical laboratory. Genet Test Mol Biomarkers. 2013; 17(7):553-61. doi: 10.1089/gtmb.2012.0118. PMID: 23631430
  4. Jabbari, J, et al. New exome data question the pathogenicity of genetic variants previously associated with catecholaminergic polymorphic ventricular tachycardia. Circ Cardiovasc Genet. 2013; 6(5):481-9. doi: 10.1161/CIRCGENETICS.113.000118. PMID: 24025405
  5. Vega, AL, et al. Protein kinase A-dependent biophysical phenotype for V227F-KCNJ2 mutation in catecholaminergic polymorphic ventricular tachycardia. Circ Arrhythm Electrophysiol. 2009; 2(5):540-7. doi: 10.1161/CIRCEP.109.872309. PMID: 19843922
  6. Kimura, H, et al. Phenotype variability in patients carrying KCNJ2 mutations. Circ Cardiovasc Genet. 2012; 5(3):344-53. doi: 10.1161/CIRCGENETICS.111.962316. PMID: 22589293
  7. Priori, SG, et al. A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene. Circ. Res. 2005; 96(7):800-7. PMID: 15761194
  8. Hattori, T, et al. A novel gain-of-function KCNJ2 mutation associated with short-QT syndrome impairs inward rectification of Kir2.1 currents. Cardiovasc. Res. 2012; 93(4):666-73. PMID: 22155372

OMIM: 60681

Clinical condition
The KCNJ2 gene is associated with Andersen-Tawil syndrome (also known as long QT syndrome [LQTS] type 7), short QT syndrome (SQTS), and catecholaminergic polymorphic ventricular tachycardia (CPVT). Additionally, preliminary evidence also supports a correlation between the KCNJ2 gene and autosomal dominant atrial fibrillation (AFib; PMID: 23684683, 19862833, 21787999).

Andersen-Tawil syndrome (ATS) is a multisystem disorder that primarily involves periodic paralysis (episodic muscle weakness), cardiac arrhythmias, and dysmorphic features. The cardiac arrhythmias are ventricular and may also show prolonged QTc and enlarged U wave on electrocardiogram (ECG/EKG). These arrhythmias can result in recurrent syncope, seizure-like activity, or sudden cardiac arrest/death. Individuals with ATS usually also have a combination of physical findings that can include low-set ears, widely spaced eyes, small lower jaw, curving of the pinky finger (fifth-digit clinodactyly), webbed fingers (syndactyly), short stature, and scoliosis (MedGen UID: 327586; GeneReviews. Andersen-Tawil syndrome. https://www.ncbi.nlm.nih.gov/books/NBK1264/. Accessed June 2017).

LQTS, SQTS, and CPVT are cardiac arrhythmia conditions that primarily affects the electrical system of the heart.

  • LQTS is defined by a prolonged QTc interval and T wave abnormalities on an ECG without the presence of any known structural heart disease. Individuals with LQTS can develop a specific abnormal heart rhythm called torsade de pointes (MedGen UID: 327586; PMID: 15911703).
  • SQTS is defined by a shortened QTc interval on an ECG that may be accompanied by peaked T waves. Individuals with SQTS may have abnormal heart rhythms, including atrial and ventricular fibrillation (MedGen UID: 400662).
  • CPVT is characterized by bidirectional or polymorphic ventricular tachycardia induced by acute adrenergic activation in individuals with structurally normal hearts (PMID: 20301466).

The abnormal heart beats in these arrhythmia conditions can lead to palpitations, dizziness (pre syncope), fainting (syncope), seizure-like activity, and in some cases, sudden cardiac arrest/death, including sudden infant death syndrome (SIDS). Symptoms can present in both children and adults and may be triggered by exercise, acute emotion, homeostatic imbalance, and use of certain medications (PMID: 24093767).

AFib is a cardiac arrhythmia characterized by rapid, chaotic beats originating from the top chambers of the heart. Symptoms may include shortness of breath, palpitations, and weakness, along with an increased risk for cardiomyopathy, heart failure, or stroke (MedGen UID: 462781; PMID: 25215263).

Gene information
The KCNJ2 gene encodes the inwardly rectifying potassium channel, subfamily J, member 2 (Kir2.1), which plays a key role in a cell’s ability to generate and transmit electrical signals. The Kir2.1 protein forms ion channels that are active in skeletal and cardiac muscle. In skeletal muscle, the channels aid in the muscle contraction and relaxation that drive physical movement. In the heart, the channels help recharge the cardiac muscle after each heartbeat to maintain normal heart rhythm. Additionally, a role for KCNJ2-derived channels in bone development has been suggested but is less clear. These channels are activated by a molecule PIP2, whose binding is required for normal channel function (National Library of Medicine. Genetics Home Reference. KCNJ2 gene. https://ghr.nlm.nih.gov/gene/KCNJ2. Accessed June 2017; PMID: 17221872, 23684683).

Pathogenic variants in KCNJ2 have autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing it to their offspring. Pathogenic KCNJ2 variants can be inherited or occur de novo. Clinically, these variants exhibit reduced penetrance and variable expression (PMID: 12163457, 22589293).

Approximately 60% of individuals with ATS will have all three of the major ATS features (i.e., periodic paralysis, cardiac arrhythmias, and physical findings), while 80% of individuals with ATS will have at least two of the three major features (PMID: 12163457).

ATS is managed symptomatically with oral potassium and/or diet and lifestyle modifications for episodic weakness. Arrhythmias, present with or without the other feature of ATS, are managed depending on clinical presentation, with options including lifestyle modification, medication, surgery, and device therapy (PMID: 24093767).

Review date: June 2017

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
KCNJ2 NM_000891.2