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Alleles for Long QT Syndrome are More Often Transmitted to Daughters Than to Sons

January 2, 2007

By Sahar Bedrood B.S. and Asher Kimchi M.D.

Paris, France - Congenital long-QT syndrome is a rare cardiac disorder in which patients present with a prolongation of the QT interval of the heart rate. The patients are at risk for ventricular arrhythmias, which could lead to syncope and death. Inheritance of long-QT syndrome is autosomal dominant but can also be recessive. Mutations in the potassium-channel genes, KCNQ1 and KCNH2, cause type 1 and type 2 forms of the disease, respectively.  A female predominance has often been observed and has been attributed to an increased susceptibility to cardiac arrhythmias. Pascale Guicheney, PhD et al from the INSERM in Paris, France investigated the possibility of an unbalanced transmission of the deleterious trait to women. Their results showed a skewed segregation of the mutations from mothers to their daughters and explained how it contributes to the female predominance in long-QT syndrome. The study was published in the December 28, 2006 issue of The New England Journal of Medicine.

Previous studies have shown an abnormally high rate of maternal transmission in a number of families with the long-QT syndrome. This group of investigators conducted a retrospective study of the transmission and distribution of mutated alleles in a large number of families with long-QT syndromes who were genotyped.

The study 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. Genotyping and phenotyping were performed at each center to which the families were recruited. Mutation segregation, sex ratio and parental transmission were analyzed. Information about phenotype, such as measured QT interval, clinical symptoms and presence or absence of a family history of sudden death related to the long-QT syndrome was also measured.

Classic 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 type 2. Among 1534 descendants, the proportion of genetically affected offspring was significantly greater than that expected according to mendelian inheritance: 870 were carriers of the mutation (57%), and 664 were non-carriers (43%, P<0.001). Among 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). Their results show that the probability of inheriting a mutation for long-QT syndrome is higher than expected according to mendelian inheritance and that in maternal transmission, daughters are favored.

A possible explanation this group of researchers gave for these findings is that the locus for the long-QT syndrome type 1 is paternally imprinted, or genetically silenced during early ontogenesis. This repression of the paternally inherited mutations for long-QT syndrome type 1 leads to the observed normal mendelian transmission. However, in females there seems to be an observed positive selection of the mutated allele during gametogenesis or post-fertilization. 

The study concludes that positive 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.

Co-authors: Medea Imboden, Ph.D., Heikki Swan, M.D., Isabelle Denjoy, M.D., Irene Marijke Van Langen, M.D., Ph.D., Pivi Johanna Latinen-Forsblom, Ph.D., Carlo Napolitano, M.D., Ph.D., Vronique Fressart, M.D., Guenter Breithardt, M.D., Myriam Berthet, B.A., Silvia Priori, M.D., Ph.D., Bernard Hainque, Ph.D., Arthur Arnold Maria Wilde, M.D., Ph.D., Eric Schulze-Bahr, M.D., Ph.D., Josu Feingold, M.D., and Pascale Guicheney, Ph.D.


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