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 - Funding Information:
We thank the patients and parents for their participation in this research. We thank Dr. Jeff Otjen from Seattle Children’s Hospital, who reviewed the radiological images, and Erin Torti of GeneDx for connecting our team with referring clinicians whose patients had SF3B2 variants. The research leading to these results has received funding from NIH-NIDCD R00DC011282 (to D.L.), NIH-NIDCR RC1 DE 020270 (to C.H.), NIH-NICHD X01 HL140518-01 (to D.L.), NIH-NICDR U01 DE025862 (to D.L. and C.H.), NIH-R01DE025468 (to J.P.S.J.), and the Jean Renny Endowment for Craniofacial Research (to M.L.C.). We would like to acknowledge Dr. David Chandler of the Australian Genome Research Facility (Node Manager, Perth Australian Genome Research Facility) for his work in identifying the first linkage of the Western Australia CFM family to chromosome 11 in 2001, and Stephanie Hedges for her clinical contributions. Whole genome sequence analysis was provided by the University of Washington Center for Mendelian Genomics (UW-CMG) and was funded by NHGRI and NHLBI grants UM1 HG006493 and U24 HG008956. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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.
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U2 - 10.1038/s41467-021-24852-9
DO - 10.1038/s41467-021-24852-9
M3 - Article
C2 - 34344887
AN - SCOPUS:85112649562
VL - 12
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 4680
ER -