Long QT Syndrome via the KCNE2 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 syncope, 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 can occur 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.

LQTS is a genetically heterogeneous disorder inherited in an autosomal dominant manner. LQT6 accounts for 1-2% of all long QT syndrome cases and occurs due to heterozygous mutations in the KCNE2 gene (Splawski et al. 2000; Alders and Mannens 2012). KCNE2 encodes the potassium channel protein MinK-related peptide-1 (MiRP1) (Abbott et al. 1999). MiRP1 is expressed in the heart where it functions to regulate cardiac electrophysiology. The majority of documented causative variants are missense mutations, but frameshift and in-frame insertions and deletions have also been reported (Abbott et al. 1999; Napolitano et al. 2005).

Approximately 1-2% of all long QT syndrome cases occur due to heterozygous mutations in the KCNE2 gene (Splawsk et al. 2000; Alders and Mannens 2012).

Gross deletions and duplications in the KCNE2 gene have not been reported in patients with Long QT syndrome.

This test provides full coverage of all coding exons of the KCNE2 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).