AbstractFacial dysmorphology is a hallmark of 22q11.2 deletion syndrome (22q11DS). Nearly all affected individuals have facial features characteristic of the syndrome: a vertically long face with broad nasal bridge, narrow palpebral fissures and mild micrognathia, sometimes accompanied by facial skeletal and oropharyngeal anomalies. Despite the frequency of craniofacial dysmorphology due to 22q11.2 deletion, there is still incomplete understanding of the contribution of individual 22q11 genes to craniofacial and oropharyngeal development. We asked whether homozygous or heterozygous loss of function of single 22q11 genes compromises craniofacial and/or oropharyngeal morphogenesis related to these 22q11DS phenotypes. We found thatRanbp1, a 22q11DS gene that mediates nucleocytoplasmic protein trafficking, is a dosage-dependent modulator of craniofacial development.Ranbp1−/−embryos have variably penetrant facial phenotypes, including altered facial morphology and cleft palate. This 22q11DS-related dysmorphology is particularly evident in the midline of the facial skeleton, as evidenced by a robustly quantifiable dysmorphology of the vomer, an unpaired facial midline bone. 22q11DS-related oropharyngeal phenotypes reflectRanbp1function in both the cranial neural crest and cranial ectoderm based upon tissue-selectiveRanbp1deletion. Analyses of genetic interaction show thatRanbp1mutation disrupts BMP signaling-dependent midline gene expression and BMP-mediated craniofacial and cranial skeletal morphogenesis. Finally, midline defects that parallel those inRanbp1mutant mice are observed at similar frequencies in theLgDel22q112DS mouse model. Apparently,Ranbp1is a modulator of craniofacial development, and in the context of broader 22q11 deletion,Ranbp1mutant phenotypes mirror key aspects of 22q11DS midline facial anomalies.