The genetic architecture of long QT syndrome: A critical reappraisal

Trends Cardiovasc Med. 2018 Oct;28(7):453-464. doi: 10.1016/j.tcm.2018.03.003. Epub 2018 Mar 30.


Collectively, the completion of the Human Genome Project and subsequent development of high-throughput next-generation sequencing methodologies have revolutionized genomic research. However, the rapid sequencing and analysis of thousands upon thousands of human exomes and genomes has taught us that most genes, including those known to cause heritable cardiovascular disorders such as long QT syndrome, harbor an unexpected background rate of rare, and presumably innocuous, non-synonymous genetic variation. In this Review, we aim to reappraise the genetic architecture underlying both the acquired and congenital forms of long QT syndrome by examining how the clinical phenotype associated with and background genetic variation in long QT syndrome-susceptibility genes impacts the clinical validity of existing gene-disease associations and the variant classification and reporting strategies that serve as the foundation for diagnostic long QT syndrome genetic testing.

Keywords: Arrhythmia; Genetic testing; Genetic variation; Long QT syndrome; Sudden cardiac death.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Death, Sudden, Cardiac / etiology*
  • Genetic Markers
  • Genetic Predisposition to Disease
  • Genetic Variation*
  • Humans
  • Long QT Syndrome / complications
  • Long QT Syndrome / diagnosis
  • Long QT Syndrome / genetics*
  • Long QT Syndrome / mortality
  • Molecular Diagnostic Techniques*
  • Phenotype
  • Predictive Value of Tests
  • Risk Assessment
  • Risk Factors


  • Genetic Markers