A molecular pathway revealing a genetic basis for human cardiac and craniofacial defects

Microdeletions of chromosome 22q11 are the most common genetic defects asso ciated with cardiac and craniofacial anomalies in humans. A screen for mous e genes dependent on dHAND, a transcription factor implicated in neural cre st development, identified Ufd1, which maps to human 22q11 and encodes a pr otein involved in degradation of ubiquitinated proteins. Mouse Ufd1 was spe cifically expressed in most tissues affected in patients with 22q11 deletio n syndrome. The human UFD1L gene was deleted in all 182 patients studied wi th 22q11 deletion, and a smaller deletion of approximately 20 kilobases tha t removed exons 1 to 3 of UFD1L was found in one individual with features t ypical of 22q11 deletion syndrome. These data suggest that UFD1L haploinsuf ficiency contributes to the congenital heart and craniofacial defects seen in 22q11 deletion.