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Objective: Velopharyngeal hypotonia seems to be an important factor in velopharyngeal dysfunction in 22q11.2 deletion syndrome, but the etiology is not understood. Because TBX1 maps within the typical 22q11.2 deletion and Tbx1-deficient mice phenocopy many findings in patients with the 22q11.2 deletion syndrome, TBX1 is considered the major candidate gene in the etiology of these defects. Tbx1 heterozygosity in mice results in abnormal vocalization 7 days postnatally, suggestive of velopharyngeal dysfunction. Previous case-control studies on muscle specimens from patients and mice revealed no evidence for a myogenic cause of velopharyngeal dysfunction. Velopharyngeal muscles are innervated by cranial nerves that receive signals from the nucleus ambiguus in the brainstem. In this study, a possible neurogenic cause underlying velopharyngeal dysfunction in Tbx1 heterozygous mice was explored by determining the size of the nucleus ambiguus in Tbx1 heterozygous and wild type mice., Methods: The cranial motor nuclei in the brainstems of postnatal day 7 wild type (n=4) and Tbx1 heterozygous (n=4) mice were visualized by in situ hybridization on transverse sections to detect Islet-1 mRNA, a transcription factor known to be expressed in motor neurons. The volumes of the nucleus ambiguus were calculated., Results: No substantial histological differences were noted between the nucleus ambiguus of the two groups. Tbx1 mutant mice had mean nucleus ambiguus volumes of 4.6 million μm(3) (standard error of the mean 0.9 million μm(3)) and wild type mice had mean volumes of 3.4 million μm(3) (standard error of the mean 0.6 million μm(3)). Neither the difference nor the variance between the means were statistically significant (t-test p=0.30, Levene's test p=0.47, respectively)., Conclusions: Based on the histology, there is no difference or variability between the volumes of the nucleus ambiguus of Tbx1 heterozygous and wild type mice. The etiology of velopharyngeal hypotonia and variable speech in children with 22q11.2 deletion syndrome warrants further investigation., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)