ERG-1; ERG1; H-ERG; HERG; HERG1; Kv11.1; LQT2; SQT1
The KCNH2 gene is associated with autosomal dominant long QT syndrome (LQTS), type 2 (MedGen UID: 462293) and short QT syndrome (SQTS) (MedGen UID: 355891). Additionally, the KCNH2 gene has preliminary evidence supporting a correlation with autosomal dominant Brugada syndrome (PMID: 24400717). For information about the location of a KCNH2 variant, please visit www.invitae.com/KCNH2-topology.
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Pathogenic KCNH2 variants and are associated with ~35% of clinical cases of LQTS. They are also a rare cause of SQTS and are associated with an unknown percentage of clinical cases of BrS.
The KCNH2 gene encodes the potassium voltage-gated channel subfamily H (eag-related) member 2. The electrical activity of cardiac muscle is controlled by the movement of potassium, sodium and calcium ions across cardiac muscle cell membranes. Mutations in genes that encode potassium channels are a common cause of inherited cardiac arrhythmias.
The KCNH2 gene is associated with long QT syndrome (LQTS) type 2, short QT syndrome (SQTS), and Brugada syndrome (BrS), which are cardiac arrhythmia conditions that primarily affect the electrical system of the heart.
The abnormal heartbeats in the above arrhythmia conditions can lead to palpitations, dizziness (presyncope), fainting (syncope), seizure-like activity and, in some cases, sudden cardiac arrest/death, including sudden infant death syndrome. Symptoms can present in both children and adults and may be triggered by homeostatic imbalance or the use of certain medications (PMID: 24011539).
The KCNH2 gene encodes the alpha-subunit of the voltage-gated potassium ion channel Kv11.1 (or HERG), which conducts the rapidly-activating delayed rectifier potassium current (IKr) portion of the heartbeat. Defects affecting the function of this ion channel can delay repolarization, causing arrhythmic events. KCNH2-related SQTS and BrS result from gain-of-function variants, while loss-of-function variants cause LQTS (PMID: 19862833).
KCNH2-related LQTS, SQTS, and BrS exhibit autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing the variant on to their offspring. Carriers are at increased risk of developing KCNH2-related conditions, and it is now possible to identify at-risk relatives who can pursue testing for this specific familial variant.
KCNH2-related LQTS, SQTS, and BrS exhibit reduced penetrance, meaning that not all individuals with a pathogenic variant will develop clinical features of these conditions (PMID: 21185501, 12736279).
Screening and management recommendations include the following:
Review date: March 2018
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|