Long QT Syndrome and Jervell and Lange-Nielsen syndrome via the KCNQ1 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 KCNQ1 gene.

LQT1 accounts for about 42% of all long QT syndrome cases and occurs due to heterozygous mutations in the KCNQ1 (KvLQT1) 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). Causative mutations in KCNQ1 include missense, nonsense, splicing and regulatory variants as well as small deletions and insertions. Most mutations reside in intracellular (52%) and transmembrane (30%) domains; 12% are found in pore and 6% in extracellular segments (Splawski et al. 2000).

KCNQ1 codes for the voltage-gated potassium channel protein KvLQT1 that is highly expressed in the heart muscle and inner ear, 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. In the inner ear, these channels help maintain the proper ion balance needed for normal hearing. The KCNQ1 protein is also produced in the kidney, lung, stomach, and intestine, where it is involved in transporting molecules across cell membranes.

Mutations in KCNQ1 are inherited in an autosomal dominant mode in Jervell and Lange-Nielsen syndrome, wherein severe prolongation of the QT interval is associated with increased risk of ventricular arrhythmias and congenital deafness. KCNQ1 variants are an uncommon cause of familial atrial fibrillation, characterized by uncoordinated electrical activity in the atria, as well as short QT syndrome, wherein the cardiac muscle takes less time than usual to recharge between beats. Mutations in the KCNQ1 gene have also been associated with several other conditions related to heart rhythm abnormalities, including sudden infant death syndrome (SIDS) and acquired long QT syndrome.

Approximately 42% of all long QT syndrome cases occur due to heterozygous mutations in the KCNQ1 gene (Splawski et al. 2000).

Gross deletions and duplications in the KCNQ1 gene have been reported in patients with Long QT syndrome and Jervell and Lange-Nielsen syndrome (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the KCNQ1 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).