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

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

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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

Incomplete penetrance of LQTS mutations

In 1985 Schwartz² proposed that some patients with LQTS could present a normal QT interval duration. After the discovery of LQTS genes, the first identified mutations were associated with a high degree of correlation between the genetic defect and the clinical diagnosis with a penetrance (i.e. the percentage of gene carriers showing the clinical phenotype) close to 100%. Subsequently, however, Vincent et al demonstrated variable QT expressivity in a large LQTS genotyped kindred⁷ and we recently reported the unsuspected presence of families with a very low penetrance⁸. In this study we demonstrated that apparently “sporadic” cases could be actually hereditary since, as a consequence of low penetrance, other non-penetrant family members can be identified by molecular screening⁸.

An extreme manifestation of incomplete penetrance is the recessive pattern of inheritance manifest in few Romano-Ward patients⁹. Indeed, overcoming the classical Mendelian concept that a recessive disease is caused by the inheritance of two diseased alleles from consanguineous heterozygous parents, the evidence of a non-deaf proband with a homozygous mutation may be viewed as the consequence of the very low penetrance of the specific mutation. Accordingly, unless a “double” dose of the defect is present the defect remains silent. The fact that both parents of the homozygous individual had a normal QT interval and presented no clinical history of syncope or of ventricular arrhythmias points to the existence of abnormalities in cardiac ion channels that may be so subtle to create only a predisposition to ventricular arrhythmias.