Cardiac phenotypes in chromosome 4q-syndrome with and without a deletion of the dHAND gene

Purpose: Terminal deletions of chromosome 4q are commonly associated with cardiovascular malformations (CVMs). The dHAND gene (HAND2, heart and neural crest derivative express 2), a basic helix-loop-helix transcription factor expressed in the developing heart, maps to 4q33. A targeted deletion in mouse shows that dHAND plays an important role in heart development, suggesting that haploinsufficiency of dHAND in patients with 4q deletions may be causal for CVMs. The purpose of this study is to examine the possible association between dHAND haploinsufficiency with the CVMs that occur in patients with 4cl terminal deletions. Methods: Fluorescence in situ hybridization (FISH) was performed with a human dHAND genomic probe on five patients with terminal deletion at 4q33 or 4q34. Results: Of the three patients with a deletion of the dHAND locus, two had CVM (both valvar pulmonic stenosis). Of the two patients without a deletion of the dHAND gene, one had a small atrial septal defect noted on autopsy. In one of the patients with breakpoint on chromosome 4 assigned to 4q34.2 by GTG-banding, FISH revealed deletion of the dHAND gene. Conclusion: The results suggest that cardiac phenotypes are very variable in patients with the terminal deletion of chromosome 4q and that haploinsufficiency of the dHAND is not necessarily associated with CVMs. The correct cytogenetic interpretation of terminal chromosome deletions might be augmented by FISH.