Long QT Syndrome via the KCNH2 Gene

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). 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), KCNE1 (LQT5) and KCNE2 (LQT6), but it can also be acquired (acquired LQTS), usually as a result of pharmacological therapy. A small percentage of cases of acquired LQTS occur in people who have an underlying variation in the KCNH2 gene.

LQT2 accounts for about 45% of all long QT syndrome cases and occurs due to heterozygous mutations in the KCNH2 (HERG) gene (Splawski et al. 2000), suggesting an autosomal dominant mode of inheritance. Female predominance has often been observed and has sometimes been attributed to an increased susceptibility to cardiac arrhythmias in women (Imboden et al. 2006). KCNH2 codes for the voltage-gated potassium channel protein that is highly expressed in the heart muscle and helps transport positively charged potassium ions out of cells. In the heart, the channels are involved in recharging the cardiac muscle after each heartbeat to maintain a regular rhythm. The KCNH2 protein is also produced in nerve cells and certain immune cells (microglia) in the central nervous system. Causative mutations in KCNH2 include missense, nonsense and splicing variants as well as small deletions and insertions (Splawski et al. 2000). Causative mutations in the KCNH2 gene are also associated with acquired long QT syndrome.

Approximately 45% of all long QT syndrome cases occur due to heterozygous mutations in the KCNH2 gene (Splawski et al. 2000).

Gross deletions and duplications in the KCNH2 gene have been reported in patients with Long QT syndrome.

This test provides full coverage of all coding exons of the KCNH2 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.