TY - JOUR
T1 - Haploinsufficiency of SF3B2 causes craniofacial microsomia
AU - University of Washington Center for Mendelian Genomics
AU - Timberlake, Andrew T.
AU - Griffin, Casey
AU - Heike, Carrie L.
AU - Hing, Anne V.
AU - Cunningham, Michael L.
AU - Chitayat, David
AU - Davis, Mark R.
AU - Doust, Soghra J.
AU - Drake, Amelia F.
AU - Duenas-Roque, Milagros M.
AU - Goldblatt, Jack
AU - Gustafson, Jonas A.
AU - Hurtado-Villa, Paula
AU - Johns, Alexis
AU - Karp, Natalya
AU - Laing, Nigel G.
AU - Magee, Leanne
AU - Mullegama, Sureni V.
AU - Pachajoa, Harry
AU - Porras-Hurtado, Gloria L.
AU - Schnur, Rhonda E.
AU - Slee, Jennie
AU - Singer, Steven L.
AU - Staffenberg, David A.
AU - Timms, Andrew E.
AU - Wise, Cheryl A.
AU - Zarante, Ignacio
AU - Saint-Jeannet, Jean Pierre
AU - Luquetti, Daniela V.
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85112649562
U2 - 10.1038/s41467-021-24852-9
DO - 10.1038/s41467-021-24852-9
M3 - Article
C2 - 34344887
AN - SCOPUS:85112649562
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4680
ER -