Current advances in Holt-Oram syndrome

Holt-Oram syndrome is an autosomal-dominant condition characterized by congenital cardiac and forelimb anomalies. It is caused by mutations of the TBX5 gene, a member of the T-box family that encodes a transcription factor. Molecular studies have demonstrated that mutations predicted to create null alleles cause substantial abnormalities in both the limbs and heart, and that missense mutations of TBX5 can produce distinct phenotypes. One class of missense mutations causes significant cardiac malformations but only minor skeletal abnormalities; Others might cause extensive upper limb malformations but less significant cardiac abnormalities. Intrafamilial variations of the malformations strongly suggest that genetic background or modifier genes play an important role in the phenotypic expression of HOS. Efforts to understand the intracellular pathway of TBX5 would provide a unique window onto the molecular basis of common congenital heart diseases and limb malformations.