Long QT Syndrome and Jervell and Lange-Nielsen Syndrome via the KCNE1 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),    KCNJ2   (LQT7),    CACNA1 C   (LQT8),    CAV3  ( LQT9),   SCN4B  (LQT10),  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 variation in the  KCNE1  gene. Jervell and Lange-Nielsen Syndrome (JLNS) is characterized by congenital profound bilateral sensorineural hearing loss and long QTc, usually greater than 500 msec. If untreated, the irregular heartbeats can lead to life-threatening ventricular arrhythmias, and a high risk of sudden cardiac death (Schwartz et al. 2006). Jervell and Lange-Nielsen syndrome prevalence remains largely unknown due to the high mortality in infancy and lack of comprehensive neonatal screening methods.  KCNQ1  or KCNE1 are the only two genes in which pathogenic variants are known to cause JLNS. JLNS is usually detected during early childhood and is inherited as an autosomal recessive genetic disorder. More than half of the untreated cases of JLNS result in death before the age of 15. 

Jervell and Lange-Nielsen Syndrome is inherited in an autosomal recessive pattern. About 90 percent of Jervell and Lange-Nielsen syndrome cases are caused by mutations in the  KCNQ1  gene. KCNE1 mutations are responsible for the remaining 10 percent of cases (Schwartz et al. 2006; Tyson et al. 2000). The subtype of Jervell and Lange-Nielsen syndrome caused by mutat ions in the KCNQ1 gene is called JLNS1. Another  subtype,  JLNS2, is  caused by mutations in the    KCNE1    gene, also known as Ward-Romano syndrome, and Long QT syndrome 5. So far,    KCNE1    mutations found in JLNS are missense/nonsense (87%) and small deletion/insertion/indels (11%) (Human Gene Mutation Database).   KCNE1    (potassium voltage-gated channel, Isk-related family, member 1) belongs to the potassium channel KCNE gene family.   The   KCNE1   gene  regulates a potassium channel made up of proteins produced by the   KCNQ1   gene.  KCNE1  and KCNQ1 work togeth er to form a potassium channel that transports pos itively charged potassium ions out of cells, which is cr itical for maintaining the normal functions of the inner ear and cardiac muscle (Crump et al. 2014).

Pathogenic variants have been found in either KCNQ1 or KCNE1 in 94% of individuals with clinical JLNS undergoing molecular testing. The pathogenic variants may be located in all coding exons. Current experience indicates that 33% are compound heterozygotes (Schwartz et al 2006). About 90 percent of Jervell and Lange-Nielsen syndrome cases are caused by mutations in the KCNQ1 gene. KCNE1 mutations are responsible for the remaining 10 percent of cases (Schwartz et al. 2006; Tyson et al. 2000). Splawski et al (2000) screened 262 unrelated LQTS patients for causative variants in 5 genes: KVLQT1, HERG, SCN5A, KCNE1 and KCNE2. They reported causative variants in 68% of their subjects. Of these, 45% were in HERG, 42% in KVLQT1, 8% in SCN5A, 3% in KCNE1 and 2% in KCNE2.

Gross deletions and duplications in the KCNE1 gene have not 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 KCNE1 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).