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Haploinsufficiency of SF3B2 causes craniofacial microsomia

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 varian...

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Autores principales: 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, 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8333351/
https://www.ncbi.nlm.nih.gov/pubmed/34344887
http://dx.doi.org/10.1038/s41467-021-24852-9
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author 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
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.
author_facet 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
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.
author_sort Timberlake, Andrew T.
collection PubMed
description 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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spelling pubmed-83333512021-08-12 Haploinsufficiency of SF3B2 causes craniofacial microsomia 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 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. Nat Commun Article 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. Nature Publishing Group UK 2021-08-03 /pmc/articles/PMC8333351/ /pubmed/34344887 http://dx.doi.org/10.1038/s41467-021-24852-9 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
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
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.
Haploinsufficiency of SF3B2 causes craniofacial microsomia
title Haploinsufficiency of SF3B2 causes craniofacial microsomia
title_full Haploinsufficiency of SF3B2 causes craniofacial microsomia
title_fullStr Haploinsufficiency of SF3B2 causes craniofacial microsomia
title_full_unstemmed Haploinsufficiency of SF3B2 causes craniofacial microsomia
title_short Haploinsufficiency of SF3B2 causes craniofacial microsomia
title_sort haploinsufficiency of sf3b2 causes craniofacial microsomia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8333351/
https://www.ncbi.nlm.nih.gov/pubmed/34344887
http://dx.doi.org/10.1038/s41467-021-24852-9
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