Genetic heterogeneity of heart-hand syndromes

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 1025:1 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.