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-Gram syndrome, which is characterized by cardiac septation defec ts and radial ray limb deformity. We have recently mapped the Holt-Gra m syndrome gene defect to the long arm of human chromosome 12 in two f amilies. The role of this disease locus in the pathogenesis of related conditions such as heart-hand syndrome type III (cardiac conduction d isease accompanied by skeletal malformations) or familial atrial septa l defects is unknown. Methods and Results Clinical evaluations and gen etic linkage analyses were performed in five additional kindreds with Holt-Gram syndrome and also in one kindred with heart-hand syndrome ty pe III and one kindred with familial atrial septal defect and conducti on disease. Holt-Gram syndrome in all five kindreds mapped to chromoso me 12q2. These studies and previous data provide odds of greater than 10(25):1 that the Holt-Gram syndrome disease gene is at chromosome 12q 2, In contrast, neither the phenotypically similar disorder heart-hand syndrome type III nor the locus responsible for a familial atrial sep tal defect with atrioventricular block maps to chromosome 12q2. Conclu sions We demonstrate that heart-hand syndromes are genetically heterog eneous. Conditions that clinically appear to be partial phenocopies of Holt-Gram syndrome arise from distinct disease genes.