Long QT Syndrome Panel

Long QT syndrome (LQTS) is a heritable channelopathy characterized by prolonged cardiac repolarization that may trigger ventricular arrhythmias (torsade de pointes), recurrent syncopes, seizure, or sudden cardiac death (Alders et al. 2018. PubMed ID: 20301308). 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. PubMed ID: 11136691). 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. PubMed ID: 15367556). Long QT syndrome has an incidence of about 1 in 2500 individuals (Schwartz et al. 2009. PubMed ID: 19841298).

Pathogenic variants in LQTS-associated genes also manifest additional clinical features. Autosomal dominant Timothy syndrome is characterized by prolonged QT interval, arrhythmias, syndactyly, developmental delay, and autism spectrum disorders. Autosomal dominant CAV3 caveolinopathy may cause hypertrophic cardiomyopathy, distal myopathy, and elevated serum creatine phosphokinase. Autosomal recessive Jervell and Lange-Nielsen syndrome is characterized by prolonged QT interval and bilateral congenital deafness. Biallelic pathogenic variants in TECRL and TRDN have been reported in patients with prolonged QT interval and catecholaminergic polymorphic ventricular tachycardia.  

Advantages of genetic testing for LQTS include confirmation of diagnosis, targeted testing of other family members, and assistance with reproductive planning. An early diagnosis of LQTS followed by early medical treatment (beta-blockers, implantable cardioverter-defibrillators, and left cardiac sympathetic denervation) has been demonstrated to reduce the mortality rate (Rohatgi et al. 2017. PubMed ID: 28728690).

Long QT syndrome is primarily inherited in an autosomal dominant but may also be inherited in autosomal recessive manner or may arise de novo. In addition to inherited forms, LQTS can also be acquired (acquired LQTS), usually as a result of pharmacological therapy. 

Up to 80% of autosomal dominant long QT cases are due to heterozygous pathogenic variants in KCNQ1, KCNH2, and SCN5A (Ackerman et al. 2011. PubMed ID: 21810866). The remaining LQTS-associated genes account for less than 5-10% of cases (Alders et al. 2018. PubMed ID: 20301308). Pathogenic missense, nonsense, frameshift, and splicing variants as well as CNV events have been reported in genes associated with LQTS. De novo pathogenic variants leading to LQTS are rare. Gross deletions or duplications are relatively rare, but they have been reported in CAV3, KCNE1, KCNH2, KCNJ2, KCNQ1, SCN5A, TECRL, and TRDN (Human Gene Mutation Database). 

Pathogenic variants associated with LQTS are largely found in genes involved in cardiac ion-channels or interacting proteins that are responsible for orchestrating the action potential of the heart.

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.

It is estimated that this NGS panel can detect a pathogenic variant in approximately 80% of patients with LQTS (Taggart et al. 2007. PubMed ID: 17502575; Ackerman et al. 2011. PubMed ID: 21810866).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 100% coverage of all coding exons of the genes 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 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).