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Haploinsufficiency of SF3B2 causes craniofacial microsomia.
- Source :
-
Nature communications [Nat Commun] 2021 Aug 03; Vol. 12 (1), pp. 4680. Date of Electronic Publication: 2021 Aug 03. - Publication Year :
- 2021
-
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 <superscript>-10</superscript> ), 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 ~3% of sporadic and ~25% of familial cases.<br /> (© 2021. The Author(s).)
- Subjects :
- Adolescent
Adult
Animals
Child
Exome genetics
Female
Genetic Association Studies
Goldenhar Syndrome pathology
Humans
Infant
Male
Mutation
Neural Crest growth & development
Neural Crest pathology
Pedigree
Spliceosomes genetics
Xenopus laevis
Goldenhar Syndrome genetics
Haploinsufficiency
RNA Splicing Factors genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 12
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 34344887
- Full Text :
- https://doi.org/10.1038/s41467-021-24852-9