Long QT syndrome: beyond the causal mutation

Congenital long QT syndrome (LQTS) is caused by single autosomal-dominant mutations in a gene encoding for a cardiac ion channel or an accessory ion channel subunit. These single mutations can cause life-threatening arrhythmias and sudden death in heterozygous mutation carriers. This recognition has been the basis for world-wide staggering numbers of subjects and families counselled for LQTS and treated based on finding (putative) disease-causing mutations. However, prophylactic treatment of patients is greatly hampered by the growing awareness that simple carriership of a mutation often fails to predict clinical outcome: many carriers never develop clinically relevant disease while others are severely affected at a young age. It is still largely elusive what determines this large variability in disease severity, where even within one pedigree, an identical mutation can cause life-threatening arrhythmias in some carriers while in other carriers no disease becomes clinically manifested. This suggests that additional factors modify the clinical manifestations of a particular disease-causing mutation. In this article, potential demographic, environmental and genetic factors are reviewed, which, in conjunction with a mutation, may modify the phenotype in LQTS, and thereby determine, at least partially, the large variability in disease severity.