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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.
Female predominance among patients with the long-QT syndrome has been reported,2,3,4,5,6 and results of studies of patients with the long-QT syndrome show a persistent excess of affected women.7,8 Reasons underlying the observed female predominance have not been thoroughly explored, and unanswered questions remain. Because the QTc interval is the main criterion for a diagnosis of the long-QT syndrome, women might be more likely to receive the diagnosis because their QTc interval is longer than that of men.9 It is unclear whether the observed unbalanced distribution between men and women in the population with clinically recognized long-QT syndrome is due to ascertainment bias or whether mutations causing the long-QT syndrome might have an increased penetrance among women.
An abnormally high rate of maternal transmission has been reported in a limited number of families with the long-QT syndrome.4 However, although most investigations have focused on correlations between phenotype and genotype, on prognostic markers, or on both in patients and their family members with symptomatic long-QT syndrome,5,8,10 the transmission of mutations causing the long-QT syndrome has not been studied in a systematic manner.
Our retrospective study investigated the transmission and distribution of the mutated alleles in a large number of families with the long-QT syndrome who were genotyped, after correction for ascertainment bias. We aimed to elucidate whether the autosomal dominant mutations that cause the long-QT syndrome types 1 and 2 follow classical mendelian inheritance or whether female predominance could be influenced by an unbalanced sex ratio in the population carrying the deleterious allele.
Methods
Study Population, Genotyping, and Phenotyping
All family members with the long-QT syndrome who participated in the study gave written informed consent before the genetic and clinical investigations, in accordance with the standards of the Declaration of Helsinki and local ethics committees.
This retrospective study involving pedigrees of patients with clinically and molecularly diagnosed long-QT syndrome type 1 or type 2 is a collaborative project comprising five European referral centers. The smallest families included one parent with the long-QT syndrome and his or her fully genotyped offspring. The larger pedigrees were divided into nuclear families, consisting of the parent with the long-QT syndrome (either molecularly defined or an obligate carrier) and the offspring. All nuclear families with even one nongenotyped descendant were excluded, as were nuclear families in which two mutations for the long-QT syndrome were transmitted. We studied 240 pedigrees involving 142 distinct mutations (for details, see the Supplementary Appendix, available with the full text of this article at www.nejm.org). Our study population consisted of 484 nuclear families with the long-QT syndrome type 1 and 269 nuclear families with the long-QT syndrome type 2. Genotyping and phenotyping were performed at each center according to standard methods. Mutations were defined as variations in DNA sequence that cosegregated with the disease phenotype, that were absent in 300 unrelated control subjects from the same ethnic background as the patient, and that induced an amino acid change or a premature stop codon. Information about phenotype — consisting of the measured QTc interval, clinical symptoms, and presence or absence of a family history of sudden death related to the long-QT syndrome — was available for 885 parental and descendant carriers (480 carriers of type 1 and 405 carriers of type 2). Clinical symptoms were defined as syncope of unknown cause, an aborted cardiac arrest, or documented torsade de pointes. Phenotypic characteristics of the Finnish carriers of the KCNQ1 mutation resulting in the G589D amino acid substitution have been reported in detail elsewhere11 and were thus not included in this study.
Analysis of Mendelian Inheritance and Correction of Ascertainment Bias
The offspring of nuclear families were analyzed to determine whether mendelian distribution ratios associated with autosomal dominant inheritance were observed in children of carriers of the long-QT syndrome. For mendelian inheritance, the expected findings were that 50% of the offspring carried the mutated allele, that the sex ratio was balanced among the sibship who were carriers, and that the frequencies of maternal and paternal transmission of the mutation were similar. We corrected for single ascertainment12 to prevent bias toward families with large numbers of carriers by excluding from transmission analysis all probands in the ascertained sibships.
Statistical Analysis
We used the chi-square test to evaluate the observed distribution of offspring of parents carrying a long-QT allele. All P values were two-sided unless otherwise stated, and a P value of less than 0.05 was used to indicate statistical significance. The Bonferroni correction was applied to correct for multiple comparisons. Transmission analysis was conducted with the use of R statistical software.13 The phenotypic data (including clinical symptoms and the presence or absence of a family history of sudden death typical of the long-QT syndrome) were compared between probands and other family members carrying long-QT alleles, and the mean QTc intervals were calculated with the use of Stata SE 8.1 statistical software.
Results
Our study included 240 pedigrees of families of European origin carrying 59 mutations causing the long-QT syndrome type 1 and 83 mutations causing the long-QT syndrome type 2. By definition, probands had markedly prolonged QTc intervals (mean [±SD], 493±44 msec for the long-QT syndrome type 1 and 505±53 msec for the long-QT syndrome type 2). The majority of probands had had syncope, aborted cardiac arrests, or both, whereas the symptoms were less prevalent and the QTc intervals were less prolonged among other family members who were carriers. Among family members who were not probands, 388 carriers of the long-QT syndrome type 1 had a mean QTc interval of 465±32 msec, and only 32% were symptomatic; 316 with the long-QT syndrome type 2 had a mean QTc interval of 470±39 msec and only 35% were symptomatic. Of the pedigrees studied, 37% of those with the long-QT syndrome type 1 and 47% of those with the long-QT syndrome type 2 involved a family history of sudden death typical of the long-QT syndrome. Among the pedigrees with type 1, 50 involved the same Finnish founder mutation (KCNQ1 G589D) localized in the cytoplasmic C-terminal domain. In comparison, Fodstad et al. reported a mean QTc of 462±38 msec among carriers of that mutation, 30% of whom were symptomatic.11 Of the Finnish pedigrees of the long-QT syndrome type 1 included in our study, 20% involved a family history of sudden death.
In accordance with previous reports, we observed a marked female predominance among the 234 clinically diagnosed probands (159 [68%], vs. 75 male probands [32%]; P<0.001) (Table 1). Correction of ascertainment bias led to the exclusion from transmission analysis of 157 probands within the sibships; more female than male probands were excluded (103 vs. 54).
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Transmission analysis was then extended to all eligible nuclear families with the long-QT syndrome (753 families). Assessment of sex ratio and mutation segregation in the entire study population after correction for ascertainment bias revealed that similar numbers of females (52%) and males (48%) were born to parents with the long-QT syndrome (Table 1 and Figure 1). As in the single nuclear families, distortion of mutation transmission was observed among all nuclear families with the long-QT syndrome. More offspring than expected were born with mutations causing the long-QT syndrome type 1 (566 persons [57%]) or with type 2 (304 persons [57%]). A persistent female predominance among mutation carriers was observed in both subgroups. 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).
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Although equal numbers of maternal and paternal transmission events are expected in mendelian transmission, we observed a higher number of maternal transmissions of mutations causing the long-QT syndrome. Indeed, among 837 offspring, the deleterious allele was inherited maternally in 516 children (62%) and paternally in 321 children (38%). The high number of mothers who were carriers, however, might have led to the observed increased maternal transmission. The parental origin of the mutation for the long-QT syndrome was known for 174 of 234 probands (Table 2). In this subgroup, we observed that mutations were inherited more often from the mother (106 probands [61%]) than from the father (68 probands [39%]). Increased maternal transmission was observed among probands with the long-QT syndrome type 1 or type 2.
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We analyzed mutation segregation, sex ratio, and parental transmission in a population composed of mutation carriers and all their offspring, in which the long-QT syndrome was genetically and clinically ascertained. Classic mendelian-inheritance ratios expected for an autosomal dominant trait were not observed among the offspring of female carriers of the long-QT syndrome type 1 allele or among mothers and fathers carrying an allele for the long-QT syndrome type 2.
We investigated the nuclear families of proband-ascertained pedigrees of the long-QT syndrome for which all offspring were genotyped and applied correction for single ascertainment. By these means, we corrected for selection bias due to incomplete or sex-specific penetrance of the mutations for the long-QT syndrome, such as the underdiagnosis of asymptomatic male carriers or the higher likelihood of cardiac events, diagnosis of the long-QT syndrome, or both among women, owing to their longer QTc intervals. The applied correction for ascertainment bias resulted in the exclusion of nearly twice as many female as male probands.
Of all probands, 68% were female. This observation was in accordance with earlier evidence of the marked female predominance in symptomatic long-QT syndrome.2,3,4,6,14,15 The reasons for the increased risk among women of cardiac symptoms and of diagnosis of the long-QT syndrome on electrocardiography have been discussed at length. First, it is well established that the QTc interval is longer in women than in men.9 Thus, abnormal QT prolongation is more likely to be detected on electrocardiography in women. The biologic basis for this sex difference might be the down-regulation of expression of cardiac potassium-channel genes by female sex hormones, which has been shown to prolong the QT interval.16 Furthermore, women may be at higher risk for symptomatic arrhythmias and sudden death than men and, if cardiac events occur, may have a higher mortality rate, even after adjustment for age.17 Longer QTc intervals may predispose women to ventricular arrhythmias, torsade de pointes in particular. In addition to predisposing physiological factors, women have been shown to be more prone to torsade de pointes during exposure to QT-prolonging drugs.18 Finally, 
-adrenergic blockade has been reported to be less efficient in women with the long-QT syndrome than in men with the syndrome.19 Taken together, all these factors may contribute to the described female predominance among phenotypically affected populations.3,4,5,7,8,14,15,20,21
The main finding of our study was that meiotic drive, which results in some alleles being overrepresented, favors the transmission of mutant alleles to daughters even in subpopulations corrected for the method of proband selection. Therefore, increased penetrance of the mutation for the long-QT syndrome in women is not the only factor resulting in female predominance. The observed transmission distortion could be due to positive selection of the mutated allele during gametogenesis or during postfertilization processes. A selection bias that eliminates male carriers of the long-QT syndrome before birth could also result in an excess of genetically affected females. However, among persons with the long-QT syndrome, the greater number of mutation carriers (female and male) than noncarriers does not provide support for a negative-selection hypothesis.
Transmission distortion has previously been reported in invertebrates as well as in mammals. Specific genetic loci and molecular mechanisms involved in transmission distortion have been investigated in drosophila22 and mice.23 Genome-wide transmission distortion involving numerous genetic loci was recently reported in a consanguineous human subpopulation.24 The skewed segregation of disease-causing alleles has been described in human genetic disease mediated by expanded trinucleotide repeats25 and in recessive congenital disorders.26
Our results revealed that the paternal mutation for the long-QT syndrome type 1 is neutral and has no positive selection effect at the population level, since transmission and sex ratios were found to be in accord with mendelian inheritance. A possible explanation for this finding is that the locus for the long-QT syndrome type 1, 11p15.5, is paternally imprinted during early ontogenesis. The exclusive maternal expression of KCNQ1 has been reported for various fetal tissues.27,28 Although true gametic imprinting is thought to be conserved throughout development,29 the paternal allele for the long-QT syndrome type 1 is expressed in mature cardiac muscle, as evidenced by the occurrence of paternally inherited long-QT syndrome type 1. We suggest that repression of the paternally inherited mutations for the long-QT syndrome type 1 due to the gametic imprint leads to the observed normal mendelian transmission.
Mechanisms resulting in the positive selection of mutations for the long-QT syndrome are unknown. The mutation might confer a reproductive advantage during the maturation, fertilization, implantation, and postimplantation development of the gamete by leading to variation in potassium flow and alteration of membrane potential. Yet the positive selection of the mutated allele seems to be independent of the detrimental cardiac effect later in life.
Though the observed transmission distortion may be directly linked to the deleterious effect of the mutation for the long-QT syndrome on potassium-channel function, we cannot rule out with certainty that no hidden bias remains in our European study population, since the retrospective study design is inherently vulnerable to involuntary bias in population selection. Therefore, to shed light on these issues, future studies should be prospective and should involve systematic transmission analysis of the mutation for the long-QT syndrome in nuclear families ascertained through nonindex patients.
In conclusion, we report transmission distortion among persons with the long-QT syndrome, owing to positive selection of the mutated allele in a large population corrected for ascertainment bias and including a large proportion of asymptomatic persons. We found compelling evidence of the unbalanced transmission of the deleterious alleles causing the long-QT syndrome types 1 and 2. Our results show that the probability of inheriting a mutation for the long-QT syndrome is higher than expected according to mendelian inheritance and that in maternal transmission, daughters are favored. Therefore, the skewed segregation of the mutation from mothers to their daughters might contribute substantially to the observed female predominance in the long-QT syndrome.
Supported by the Leducq Fondation, INSERM Assistance Publique–Hôpitaux de Paris, the Deutsche Forschungsgesellschaft (Schu1082/3-1), the Interuniversity Cardiology Institute of the Netherlands (project 27), the Dutch Heart Foundation (2000.195), Telethon (GGP04066), Ricerca Finalizzata (2003/180), Fondo Investimenti Ricerca Biotechnologica (RBNE01XMP4_006), and Confinanziamento Ministeriale (2001067817_003).
No potential conflict of interest relevant to this article was reported.
We are indebted to a large number of clinicians, geneticists, molecular biologists, and skillful technicians in the molecular diagnostic departments of the five participating European referral centers for the long-QT syndrome.
Source Information
From INSERM, Institut de Myologie, Université Pierre et Marie Curie, Institut Fédératif de Recherche 14 and Groupe Hospitalier Pitié–Salpêtrière (M.I., I.D., M.B., B.H., P.G.); Service de Cardiologie, Hôpital Lariboisière (I.D.); and Service de Biochimie (V.F., B.H., P.G.) and Département de Génétique (J.F.), Groupe Hospitalier Pitié–Salpêtrière — all at the Assistance Publique–Hôpitaux de Paris, Paris; the Department of Molecular Epidemiology, Institute of Social and Preventive Medicine, University of Zurich, Zurich, Switzerland (M.I.); the Department of Medicine, University of Helsinki, Helsinki (H.S., P.J.L.-F.); the Experimental and Molecular Cardiology Group and Department of Clinical Genetics, Academic Medical Center, Amsterdam (I.M.V.L., A.A.M.W.); Molecular Cardiology Laboratories, Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Salvatore Maugeri and the University of Pavia, Pavia, Italy (C.N., S.P.); and the Leibniz Institute for Arteriosclerosis Research, Department of Molecular Cardiology, University of Münster, and the Department of Cardiology and Angiology, Hospital of the University of Münster — both in Münster, Germany (G.B., E.S.-B.).
Address reprint requests to Dr. Guicheney at INSERM, Unité 582, Institut de Myologie, Groupe Hospitalier Pitié–Salpêtrière, 47 Blvd. de l'Hôpital, F-75013, Paris, France, or to Dr. Imboden at imboden{at}medgen.unizh.ch.
References
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Related Letters:
Long-QT Syndrome
Naumova A. K., Guicheney P., Imboden M.
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N Engl J Med 2007;
356:1680, Apr 19, 2007.
Correspondence
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