Haploinsufficiency of SF3B2 causes craniofacial microsomia
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2021-08-03Autore
Timberlake, Andrew T.Griffin, Casey
Heike, Carrie L.
Hing, Anne V.
Cunningham, Michael L.
Chitayat, David
Davis, Mark R.
Doust, Soghra J.
Drake, Amelia F.
Duenas-Roque, Milagros M.
Goldblatt, Jack
Gustafson, Jonas A.
Hurtado-Villa, Paula
Johns, Alexis
Karp, Natalya
Laing, Nigel G.
Magee, Leanne
University of Washington Center for Mendelian Genomics
Mullegama, Sureni V.
Pachajoa, Harry
Porras-Hurtado, Gloria L.
Schnur, Rhonda E.
Slee, Jennie
Singer, Steven L.
Staffenberg, David A.
Timms, Andrew E.
Wise, Cheryl A.
Zarante, Ignacio
Saint-Jeannet, Jean-Pierre
Luquetti, Daniela V.
Autore/i aziendale
Pontificia Universidad Javeriana. Facultad de Medicina. Instituto de Genética Humana. Grupo de investigación Instituto de Genética Humana
Pontificia Universidad Javeriana. Facultad de Medicina. Hospital Universitario San Ignacio
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Artículo de revista
ISSN
2041-1723
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Sommario
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 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.
Parole chiave
Rna Splicing FactorSf3B2 Protein, Human
Adolescent
Adult
Animal
Child
Exome
Female
Genetic Association Study
Genetics
Goldenhar Syndrome
Growth, Development And Aging
Haploinsufficiency
Human
Infant
Male
Mutation
Neural Crest
Pathology
Link alla risorsa
https://www.nature.com/articles/s41467-021-24852-9Editoriale
Nature Communications; Volumen 12 , Páginas 1 - 11 (2021)
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