Genetic Heterogeneity of Heart-Hand Syndromes

Abstract

Background Heart-hand syndromes compose a class of combined congenital cardiac and limb deformities. The prototypical heart-hand disorder is Holt-Oram syndrome, which is characterized by cardiac septation defects and radial ray limb deformity. We have recently mapped the Holt-Oram syndrome gene defect to the long arm of human chromosome 12 in two families. The role of this disease locus in the pathogenesis of related conditions such as heart-hand syndrome type III (cardiac conduction disease accompanied by skeletal malformations) or familial atrial septal defects is unknown. Methods and Results Clinical evaluations and genetic linkage analyses were performed in five additional kindreds with Holt-Oram syndrome and also in one kindred with heart-hand syndrome type III and one kindred with familial atrial septal defect and conduction disease. Holt-Oram syndrome in all five kindreds mapped to chromosome 12q2. These studies and previous data provide odds of greater than 10 25 :1 that the Holt-Oram syndrome disease gene is at chromosome 12q2. In contrast, neither the phenotypically similar disorder heart-hand syndrome type III nor the locus responsible for a familial atrial septal defect with atrioventricular block maps to chromosome 12q2. Conclusions We demonstrate that heart-hand syndromes are genetically heterogeneous. Conditions that clinically appear to be partial phenocopies of Holt-Oram syndrome arise from distinct disease genes.