Outside the brain, the 22q11DS and 22q11DupS manifest considerable phenotypic overlap, including congenital heart defects, palatal defects and abnormal facies, micrognathia, short stature, dysplastic ears and hearing defects, down-slanting palpebral fissures, urogenital anomalies, absent thymus, T cell deficiency, anomalies of the hands and feet, and scoliosis, suggesting diverse effects of both low and high copy numbers [23]. Mouse studies indicate that many of the physical anomalies associated with copy number variation at 22q11.2 are attributable to Tbx1 dosage [24]. Mutations in the GDF6 gene, which is expressed in the developing intervertebral space, are causative for the KF2 class of KFS [25]. Tbx1 is likewise expressed in the developing intervertebral space [25, 26]. The 22q11DS has shown prior association with synostosis in the appendages, scoliosis, and vertebral irregularities [9]; however, this is the first report of vertebral fusion in association with duplication or deletion at 22q11.2. We propose Tbx1 as a candidate gene for broad spectrum KFS where it presents in association with Sprengle's shoulder, heart, and palatal and/or urogenital anomalies.
