Pre-Test Probability and Genes and Variants of Uncertain Significance in Familial Long QT Syndrome

Kathryn E. Waddell-Smith, Jonathan R. Skinner, J. Martijn Bos

Research output: Contribution to journalReview articlepeer-review

8 Citations (Scopus)


The genetics underlying familial long QT syndrome (LQTS) are among the best characterised of all of the inherited heart conditions. Cohort and registry studies have demonstrated important genotype-phenotype correlations that are now essential in guiding clinical practice of patients with the most common three genotypes; KCNQ1 (LQT type 1), KCNH2 (LQT type 2) and SCN5A (LQT type 3). However, the growing number of genes—now more than 16—is confusing, and there is much doubt as to whether many actually cause LQTS at all. Furthermore, changes in sequencing techniques, evolving variant classification criteria and new scientific discoveries make all genes and variants subject to a continuous process of re-classification. This review discusses the nature of variant adjudication, the important concept of pre-test probability in interpreting a genetic result and how the nomenclature of LQTS is shifting in response to this new knowledge. It further discusses the role of deep phenotyping, the inclusion of evaluation of family members in interpreting a genetic test result, or even deciding if genetic testing should occur at all, and the role of specialist multidisciplinary teams to translate this continuously evolving knowledge into the best clinical advice, in partnership with referring cardiologists.

Original languageEnglish
Pages (from-to)512-519
Number of pages8
JournalHeart, Lung and Circulation
Issue number4
Publication statusPublished - Apr 2020


  • Cohort registry
  • Genetic testing
  • Genetics
  • Genotype-phenotype correlations
  • Long QT syndrome


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