Bedrood B.S. and Asher Kimchi M.D.
- 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
Journal of Medicine.
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.
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.
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.
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
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.
Medea Imboden, Ph.D., Heikki Swan, M.D., Isabelle Denjoy, M.D.,
Irene Marijke Van Langen, M.D., Ph.D., Päivi Johanna
Latinen-Forsblom, Ph.D., Carlo Napolitano, M.D., Ph.D.,
Véronique 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., Josué Feingold, M.D., and Pascale