14th International Congress
THE "NEW FRONTIERS"
OF ARRHYTHMIAS 2000

Jan. 29 - Feb. 5, 2000
Marilleva, Trento, Italy

RT-18

Low penetrance mutations and compound heterozygosity in LQTS: phenotypic consequences and implications for the clinical presentation of the disease

Carlo Napolitano, Raffaella Bloise, Elena Ronchetti, Mirella Memmi, Peter J Schwartz*, Silvia G. Priori.
Laboratories, Fondazione Salvatore Maugeri IRCCS, Pavia, *Dept of Cardiology, Policlinico S. Matteo IRCCS, Pavia, Italy

Introduction

The long QT syndrome (LQTS) is a inherited form of cardiac arrhythmias caused by genetically determined defects in transmembrane ion channel forming proteins¹. The clinical phenotype of LQTS is characterized by prolongation of the QT interval at the surface ECG and high risk of sudden cardiac death secondary to episodes of TdP ventricular tachycardia^2,3.

Six genes, when mutated, have the potential to induce the LQTS phenotype KvLQT1, HERG, SCN5A, KCNE1, KCNE2^1,4, and different mutations have been reported throughout the coding region of these genes in several families, thus indicating a remarkable genetic heterogeneity.

It is common experience for the physicians that the clinical manifestations of LQTS may be highly variable, going from patients presenting with markedly prolonged QT interval, repeated episodes of loss of consciousness and cardiac arrest requiring aggressive therapy, to patients who remain asymptomatic despite the QT interval prolongation. Among the same line, QT interval duration in LQTS patients may be extremely increased (e.g. >600 ms) but only borderline increased in other cases.

Overall, the evidence of the genotypic and phenotypic variability in LQTS could lead to hypothesize that the specific phenotypes (e.g. a severe clinical presentation) are correlated to specific mutations. However, this hypothesis has been at least partially dismissed after the demonstration that even among patients carrying the same molecular defect, and also within the same family, the clinical manifestations of the disease may be very different^5,6.

The reasons of the lack of predictable of specific genotype-phenotype correlation in the LQTS may be the variable penetrance and incomplete expressivity of some LQTS mutations or the presence of genetic or environmental modifier factors, contributing to the modulation of the clinical manifestation of the disease.

In this article we will summarize the evidence showing how the inherited ion channel defects may be responsible for a wide range of clinical manifestations, with particular focus on the consequences of their variable penetrance.

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