Haploinsufficiency of SF3B2 causes craniofacial microsomia

Craniofacial microsomia (CFM) is the second most common congenital facial anomaly, yet its genetic etiology remains unknown. We perform whole-exome or genome sequencing of 146 kindreds with sporadic (n=138) or familial (n=8) CFM, identifying a highly significant burden of loss of function variants in SF3B2 (P=3.8 x 10(-10)), a component of the U2 small nuclear ribonucleoprotein complex, in probands. We describe twenty individuals from seven kindreds harboring de novo or transmitted haploinsufficient variants in SF3B2. Probands display mandibular hypoplasia, microtia, facial and preauricular tags, epibulbar dermoids, lateral oral clefts in addition to skeletal and cardiac abnormalities. Targeted morpholino knockdown of SF3B2 in Xenopus results in disruption of cranial neural crest precursor formation and subsequent craniofacial cartilage defects, supporting a link between spliceosome mutations and impaired neural crest development in congenital craniofacial disease. The results establish haploinsufficient variants in SF3B2 as the most prevalent genetic cause of CFM, explaining similar to 3% of sporadic and similar to 25% of familial cases.

Automated summary

Craniofacial microsomia (CFM) is the second most common congenital facial anomaly, with loss of function variants in SF3B2 identified as a significant genetic cause in the study. The findings suggest a link between SF3B2 mutations, impaired neural crest development, and the development of CFM.