Ignacio Zarante

Haploinsufficiency of SF3B2 causes craniofacial microsomia

Publisher: Springer Science and Business Media LLC

Date: 03-08-2021

DOI: 10.1038/S41467-021-24852-9

Abstract: 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 × 10 −10 ), a component of the U2 small nuclear ribonucleoprotein complex, in probands. We describe twenty in iduals 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 ~3% of sporadic and ~25% of familial cases.

Congenital Malformations Surveillance Programme Of Bogotá

Location: Colombia

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Asociación Colombiana De Médicos Genetistas Y Medicina Genómica

Location: Colombia

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Pontificia Universidad Javeriana

Location: Colombia

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Hospital Universitario San Ignacio

Location: Colombia

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