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KCNH2

Alias

ERG-1; ERG1; H-ERG; HERG; HERG1; Kv11.1; LQT2; SQT1

Associated disorders

The KCNH2 gene is associated with autosomal dominant long QT syndrome (LQTS), type 2 (MedGen UID: 462293), short QT syndrome (SQTS) (MedGen UID: 355891) and Brugada syndrome (BrS) (MedGen UID: 222975).

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KCNH2

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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.

OMIM: 152427

Clinical condition
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.

  • 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 (PMID: 24011539).
  • SQTS is defined by a shortened QTc interval on an ECG. Individuals with SQTS can develop irregular and rapid heart rhythms initiating from the top (atrial) or bottom (ventricular) chambers of the heart (PMID: 24011539).
  • BrS is defined by characteristic ST-segment elevations on an ECG, specifically in leads V1 and V2 (PMID: 24011539).

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).

Gene information
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).

Inheritance
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).

Management
Screening and management recommendations include the following:

  • Cardiac examination including calculation of QTc (PMID: 29097296, 24011539)
  • Management recommendations for KCNH2-related arrhythmia depend on clinical presentation and may include:
    • lifestyle modification, including avoidance of certain sports, activities, medications (www.crediblemeds.org), or startling noises, and maintenance of homeostatic balance (PMID: 11136691, 24011539)
    • medications (PMID: 29097296, 24011539)
    • device therapy (e.g., pacemaker, implantable defibrillator; PMID:29097296, 24011539)
    • surgical therapy (e.g., denervation; PMID:29097296, 24011539)
  • Clinical genetics consultation to discuss genetic testing for at-risk family members and reproductive risks (PMID: 29097296, 24011539)

Review date: March 2018

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, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
KCNH2 NM_000238.3; NM_172057.2