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We perform whole-exome or genome sequencing of 146 kindreds with sporadic (n\u2009=\u2009138) or familial (n\u2009=\u20098) CFM, identifying a highly significant burden of loss of function variants in <jats:italic>SF3B2<\/jats:italic> (P\u2009=\u20093.8 \u00d7 10<jats:sup>\u221210<\/jats:sup>), 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 <jats:italic>SF3B2<\/jats:italic>. 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 <jats:italic>SF3B2<\/jats:italic> in <jats:italic>Xenopus<\/jats:italic> 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 <jats:italic>SF3B2<\/jats:italic> as the most prevalent genetic cause of CFM, explaining ~3% of sporadic and ~25% of familial cases.<\/jats:p>","DOI":"10.1038\/s41467-021-24852-9","type":"journal-article","created":{"date-parts":[[2021,8,3]],"date-time":"2021-08-03T10:03:01Z","timestamp":1627984981000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":88,"title":["Haploinsufficiency of SF3B2 causes craniofacial microsomia"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8926-9692","authenticated-orcid":false,"given":"Andrew 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