Long QT Syndrome via the KCNJ5 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). 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), KCN J2 (LQT7), CACNA1C (LQT8), CAV3 (LQT9), SCN4B (L QT10), 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 pathogenic variant in the KCNJ5 gene.

Long QT syndrome type 13 (LQT13) is caused by loss-of-function mutation in KCNJ5 and is inherited in an autosomal dominant manner. The protein encoded by KCNJ5 is an integral membrane protein, inward-rectifier type potassium channel and is controlled by G-proteins (Yang et al. 2010). Neuronal and cardiac G-protein-coupled inward rectifier potassium (Girk) channels are homo- and hetero-tetrameric complexes formed by subunits encoded by four genes named Girk1–4 /Kir3.1–4/KCNJ3, KCNJ6 , KCNJ9 and KC NJ5. Cardiac IKACh channels are complexes consisting of Girk1 (KCNJ3) and Girk4 (KCNJ5) (Wickman et al. 1999). IKACh channels are predominantly expressed in the sinoatrial node, atria, and atrioventricular node. Biochemical and genetic studies have demonstrated that IKACh plays an important role in both parasympathetic slowing of the heart rate and repolarization of atrial action potentials (Mesirca et al. 2013). Besides Long QT syndrome, pathogenic variants in KCNJ5 also cause Familial Hyperaldosteronism (Human Gene Mutation Database). To date, all reported pathogenic variants are missense variants.

Up to 70 % of patients with a clinical diagnosis of Long QT syndrome have identifiable pathogenic variants (Beckmann et al. 2013). The majority of LQTS cases are caused by pathogenic variants in one of three genes: KCNQ1, KCNH2 and SCN5A. Pathogenic variants in the following genes: ANK2, KCNE1, KCNE2, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP9, SNTA1 and KCNJ5 together cause about 5% of LQTS (Lieve et al. 2012; Kapplinger et al. 2009).

To date, no gross deletions or duplications have been reported in KCNJ5 (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the KCNJ5 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).