Phenotypic characterization of a family with long QT syndrome 13: A different type of variable penetrance

Abstract

Congenital long QT syndrome (LQTS) is an uncommon disorder with a prevalence of 1:2500 in the general population. LQTS is a disease of cardiac repolarization defined by 2 characteristics: (1) prolonged heart-rate corrected QT (QTc) interval on a resting surface electrocardiogram (ECG) and (2) the presence of torsades de pointes ventricular tachycardia and/or ventricular fibrillation with associated cardiac events. The first cases of LQTS were described 50 years ago, and over the next 30 years several dedicated investigators worked to understand the pathological mechanisms underlying this disease. The landmark discoveries by Mark Keating’s group that rare variants in genes encoding for cardiac ion channels can act as diseasecausing mutations in families with LQTS clearly defined the primary contribution of ion channel dysfunction in the pathogenesis of this disease. Furthermore, these exciting discoveries created a large amount of interest in LQTS since the phenotype-genotype relationship could be identified and connected to each other. In this case, one phenotype marker is readily assessible as a prolonged QTc interval on the surface ECG, and the genotype is a point mutation in a single well-defined gene. Thus far, disease-causing mutations in 16 genes have been associated with LQTS and genetic screening is now available that can identify the disease-causing gene in 80% of the cases. Knowing who is affected can exclude disease in genotype-negative patients, or help determine the prognosis and guide therapy for genotype-positive patients. However, it was appreciated early on that the symptoms and phenotype of LQTS spanned a broad spectrum and that the penetrance of LQTS is relatively low. Many patients with confirmed disease-causing mutations do not have symptoms or significant QTc interval prolongation, while other affected patients with subtle QTc interval prolongation experience profound symptoms or fatal events. The reason why mutations in the known LQTS diseasecausing genes do not always present as manifest disease is that modifying factors also contribute to the pathogenesis of