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Editor—Congenital heart disease occurs commonly. One form, heterotaxy, accounts for approximately 3-4% of the total incidence and has a mortality rate approaching 45%.1Given that the diagnosis is based on the discordance of the left-right (LR) sidedness between the abdominal viscera and atria,2heterotaxy describes a group of malformations arising from the abnormal development of LR asymmetry.3
In familial cases one can find subjects with complete, mirror image reversal of normal LR anatomy (situs inversus), and others who manifest the hallmark visceroatrial discordance as well as other laterality malformations (sometimes collectively called situs ambiguus). Moreover other family members with normal LR anatomy (situs solitus) are obligate disease gene carriers by virtue of their pedigree position.
Many genes have been implicated in normal and abnormal LR axis development among non-human vertebrates.4 Knowledge remains sparse, however, regarding the molecular genetics of human LR malformations. Positional cloning identified a gene,ZIC3, on chromosome Xq24-27.1, in which mutations have been found among one sporadic and six familial cases of LR axis malformations.5 A few mutations have also been found in LEFTYA and in the activin receptor type IIB gene (ACVR2B), identified on the basis of their homology to the corresponding genes known to cause laterality defects in the mouse.6 7
Here we describe a family in which LR malformations segregate across five generations. Although male to male transmission has not occurred, males and females appear to be affected similarly, and linkage analysis has excluded a disease locus on the X chromosome (see below). Both situs inversus and situs ambiguus are found in seven affected subjects and pedigree position implicates four apparently normal subjects as obligate gene carriers. These observations strongly support a model of autosomal dominant inheritance with reduced penetrance. The pedigree comprising 36 subjects …