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Female predominance and transmission distortion in the long-QT syndrome


Imboden, M; Swan, H; Denjoy, I; Van Langen, I M; Latinen-Forsblom, P J; Napolitano, C; Fressart, V; Breithardt, G; Berthet, M; Priori, S; Hainque, B; Wilde, A A M; Schulze-Bahr, E; Feingold, J; Guicheney, P (2006). Female predominance and transmission distortion in the long-QT syndrome. New England Journal of Medicine, 355(26):2744-51.

Abstract

BACKGROUND: Congenital 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. METHODS: We 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. RESULTS: 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 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. CONCLUSIONS: 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.

Abstract

BACKGROUND: Congenital 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. METHODS: We 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. RESULTS: 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 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. CONCLUSIONS: 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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Epidemiology, Biostatistics and Prevention Institute (EBPI)
Dewey Decimal Classification:610 Medicine & health
Date:2006
Deposited On:13 May 2009 10:34
Last Modified:05 Apr 2016 13:13
Publisher:Massachusetts Medical Society
ISSN:0028-4793
Publisher DOI:https://doi.org/10.1056/NEJMoa042786
Official URL:http://content.nejm.org/cgi/content/full/355/26/2744
PubMed ID:17192539

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