• Medea Imboden, Heikki Swan, Isabelle Denjoy, Irene Marijke Van Langen, Päivi Johanna Latinen-Forsblom, Carlo Napolitano, Véronique Fressart, Guenter Breithardt, Myriam Berthet, Silvia Priori, Bernard Hainque, Arthur Arnold Maria Wilde, Eric Schulze-Bahr, Josué Feingold, and Pascale Guicheney.
• INSERM, Institut de Myologie, Université Pierre et Marie Curie, Institut Fédératif de Recherche 14 and Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
• N. Engl. J. Med. 2006 Dec 28; 355 (26): 2744-51.

BackgroundCongenital long-QT syndrome is a disorder resulting in ventricular arrhythmias and sudden death. The most common forms of the long-QT syndrome, types 1 and 2, are caused by mutations in the potassium-channel genes KCNQ1 and KCNH2, respectively. Although inheritance of the long-QT syndrome is autosomal dominant, female predominance has often been observed and has been attributed to an increased susceptibility to cardiac arrhythmias in women. We investigated the possibility of an unbalanced transmission of the deleterious trait.MethodsWe investigated the distribution of alleles for the long-QT syndrome in 484 nuclear families with type 1 disease and 269 nuclear families with type 2 disease, all with fully genotyped offspring. The families were recruited in five European referral centers for the long-QT syndrome. Mutation segregation, sex ratio, and parental transmission were analyzed after correction for single ascertainment.ResultsClassic mendelian inheritance ratios were not observed in the offspring of either female carriers of the long-QT syndrome type 1 or male and female carriers of the long-QT syndrome type 2. Among the 1534 descendants, the proportion of genetically affected offspring was significantly greater than that expected according to mendelian inheritance: 870 were carriers of a mutation (57%), and 664 were noncarriers (43%, P<0.001). Among the 870 carriers, the allele for the long-QT syndrome was transmitted more often to female offspring (476 [55%]) than to male offspring (394 [45%], P=0.005). Increased maternal transmission of the long-QT syndrome mutations to daughters was also observed, possibly contributing to the excess of female patients with autosomal dominant long-QT syndrome.ConclusionsPositive selection of the mutated alleles that cause the long-QT syndrome leads to transmission distortion, with increased proportions of mutation carriers among the offspring of affected families. Alleles for the long-QT syndrome are more often transmitted to daughters than to sons.Copyright 2006 Massachusetts Medical Society.

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