1. Mutations in FOXI3 Cause Microtia and Craniofacial Microsomia

PURPOSE: Craniofacial microsomia (CFM) represents a spectrum of craniofacial malformation, ranging from isolated microtia with or without aural atresia to underdevelopment of the mandible, maxilla, orbit, facial soft tissue, and/or facial nerve. The genetic causes of CFM remain largely unknown. METHODS: We performed whole exome or whole genome sequencing of 415 kindreds with microtia/CFM spectrum phenotypes. RESULTS: We studied a five generation kindred with microtia, identifying a missense mutation in FOXI3 (p.R236W) as the cause of disease (LOD=3.33). We subsequently identified 6 individuals from 3 additional kindreds with microtia-CFM spectrum phenotypes harboring mutations in FOXI3, a regulator of ectodermal and neural crest development. Missense mutations in the nuclear localization sequence were identified in cases with isolated microtia with aural atresia, and loss of function mutations were found in CFM patients, suggesting dosage sensitivity. Mutations were found to affect subcellular localization of FOXI3. CONCLUSIONS: The results define mutations in FOXI3 as a frequent genetic cause of CFM. Mutations in FOXI3 and previously identified SF3B2 cumulatively cause 6% of CFM cases, including ~40% of familial cases. The results support genetic testing for FOXI3 mutations in patients with grade II/III microtia with atresia, with appropriate genetic counseling provided for those found to harbor pathogenic mutations. These findings contribute to a growing body of evidence supporting neural crest disruption as the predominant cause of CFM.