Haploinsufficiency of SF3B2 causes craniofacial microsomia

Andrew T. Timberlake (), Casey Griffin, Carrie L. Heike, Anne V. Hing, Michael L. Cunningham, David Chitayat, Mark R. Davis, Soghra J. Doust, Amelia F. Drake, Milagros M. Duenas-Roque, Jack Goldblatt, Jonas A. Gustafson, Paula Hurtado-Villa, Alexis Johns, Natalya Karp, Nigel G. Laing, Leanne Magee, Sureni V. Mullegama, Harry Pachajoa, Gloria L. Porras-Hurtado, Rhonda E. Schnur, Jennie Slee, Steven L. Singer, David A. Staffenberg, Andrew E. Timms, Cheryl A. Wise, Ignacio Zarante, Jean-Pierre Saint-Jeannet and Daniela V. Luquetti ()
Additional contact information
Andrew T. Timberlake: NYU Langone Medical Center
Casey Griffin: New York University College of Dentistry
Carrie L. Heike: University of Washington
Anne V. Hing: University of Washington
Michael L. Cunningham: University of Washington
David Chitayat: University of Toronto
Mark R. Davis: QEII Medical Centre, Hospital Avenue
Soghra J. Doust: Genetics Program, Peterborough Regional Health Centre
Amelia F. Drake: University of North Carolina
Milagros M. Duenas-Roque: Hospital Edgardo Rebagliati Martins
Jack Goldblatt: King Edward Memorial Hospital
Jonas A. Gustafson: University of Washington
Paula Hurtado-Villa: Pontificia Universidad Javeriana and Centro Médico Imbanaco
Alexis Johns: Children’s Hospital Los Angeles
Natalya Karp: Department of Pediatrics, London Health Sciences Centre, Division of Medical Genetics, Western University
Nigel G. Laing: University of Western Australia
Leanne Magee: Children’s Hospital of Philadelphia
Sureni V. Mullegama: GeneDx
Harry Pachajoa: Universidad Icesi and Fundacion Clinica Valle del Lili
Gloria L. Porras-Hurtado: Clinica Comfamiliar Risaralda
Rhonda E. Schnur: GeneDx
Jennie Slee: King Edward Memorial Hospital
Steven L. Singer: Perth Children’s Hospital
David A. Staffenberg: NYU Langone Medical Center
Andrew E. Timms: Seattle Children’s Research Institute
Cheryl A. Wise: QEII Medical Centre, Hospital Avenue
Ignacio Zarante: Pontificia Universidad Javeriana
Jean-Pierre Saint-Jeannet: New York University College of Dentistry
Daniela V. Luquetti: University of Washington

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: 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 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.

Date: 2021
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-021-24852-9 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24852-9

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-24852-9

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().