Genes and mechanisms of heterotaxy: patients drive the search

Heterotaxy, a disorder in which visceral organs, including the heart, are mispatterned along the left-right body axis, contributes to particularly severe forms of congenital heart disease that are difficult to mitigate even despite surgical advances. A higher incidence of heterotaxy among individuals with blood kinship and the existence of rare monogenic disease forms suggest the existence of a genetic component, but the genetic and phenotypic heterogeneity of the disease have rendered gene discovery challenging. Next generation genomics in patients with syndromic, but also non-syndromic and sporadic heterotaxy, have recently helped to uncover new candidate disease genes, expanding the pool of genes already identified via traditional animal studies. Further characterization of these new genes in animal models has uncovered fascinating mechanisms of left-right axis development. In this review, we will discuss recent findings on the functions of heterotaxy genes with identified patient alleles.