Correspondence
Long-QT Syndrome
N Engl J Med 2007; 356:1680April 19, 2007
- Article
To the Editor:
Imboden et al. (Dec. 28 issue)1 report preferential transmission of mutant alleles in the KCNQ1 gene (11p15.5) from mothers to daughters and propose that these mutations confer a selective reproductive advantage. However, allele-specific transmission-ratio distortion2 and grandparental-origin–dependent transmission-ratio distortion3 have been described previously for 11p15.5.2,3 Specifically, the 11p15.5 alleles of a maternal grandmother are more likely (61%) to be transmitted to her granddaughters than to her grandsons.3 The transmission of 11p15.5 alleles that is dependent on their grandparental origin is consistent with these observations.1 Indeed, if females are more likely to be affected, the mutant KCNQ1 alleles may be more likely to have originated with the grandmother in these families. The observed bias in their transmission may be associated with the grandparental origin of the alleles rather than with the reproductive advantage of the mutations. I would predict, therefore, that in families in which the mutation has been inherited from the maternal grandmother, preferential transmission would be detected, whereas in families in which the mutation originated in the grandfather, transmission to female offspring would be less likely.
3 ReferencesAnna K. Naumova, Ph.D.
McGill University, Montreal, QC H3A 1A1, Canada
anna.naumova@muhc. mcgill. ca 1
Imboden M ,Swan H ,Denjoy I , et al. Female predominance and transmission distortion in the long-QT syndrome. N Engl J Med 2006;355:2744-2751
Full Text | Web of Science | Medline2
Eaves IA ,Bennett ST ,Forster P , et al. Transmission ratio distortion at the INS-IGF2 VNTR. Nat Genet 1999;22:324-325
CrossRef | Web of Science | Medline3
Naumova AK ,Greenwood CMT ,Morgan K . Imprinting and deviation from Mendelian transmission ratios. Genome 2001;44:311-320
CrossRef | Web of Science | Medline
Author/Editor Response
Naumova and her colleagues previously reported transmission distortion for imprinted chromosomal regions including the locus for the long-QT syndrome type 1, 11p15.5.1 They suggested that imprinting defects and selective embryonic loss could lead to the skewed transmission and that 11p15.5 alleles were transmitted preferentially from grandmothers to granddaughters. However, they also reported a favored transmission of alleles from maternal grandfathers and paternal grandmothers to grandsons.
We have reported that the increased transmission of long-QT syndrome types 1 and 2 from mothers to daughters contributes to the female predominance in this disease, and we have suggested a positive selection of mutation carriers in general. Although parent-of-origin methylation patterns might be involved in the transmission distortion observed at the locus for long-QT syndrome type 1, it is not clear how the selective loss of embryos might relate to preferential transmission of the mutated long-QT syndrome type 1 allele from mothers to their offspring. Differences in the transmission ratios between long-QT syndrome types 1 and 2 that are specific to the sex of the offspring suggest that more than one mechanism might lead to transmission distortion. In addition, the long-QT syndrome type 2 locus (7q35-q36) is not known to be imprinted. Further studies investigating mechanisms of non-mendelian transmission in human disease and embryonic development are certainly needed.
1 ReferencesPascale Guicheney, Ph.D.
INSERM Unité 582, F-75013 Paris, FranceMedea Imboden, Ph.D.
University of Zurich, CH-8006 Zurich, Switzerland
imboden@medgen.unizh. ch 1
Naumova AK ,Greenwood CMT ,Morgan K . Imprinting and deviation from Mendelian transmission ratios. Genome 2001;44:311-320
CrossRef | Web of Science | Medline
