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PMID: 22366783 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome.

Nature genetics ·Vol. 44 ·No. 4 ·2012-02-26 ·Pages 440-4, S1-2

Rivière JB, van Bon BW, Hoischen A, Kholmanskikh SS, O'Roak BJ, Gilissen C, Gijsen S, Sullivan CT, Christian SL, Abdul-Rahman OA, Atkin JF, Chassaing N, Drouin-Garraud V, Fry AE, Fryns JP, Gripp KW, Kempers M, Kleefstra T, Mancini GM, Nowaczyk MJ, van Ravenswaaij-Arts CM, Roscioli T, Marble M, Rosenfeld JA, Siu VM, de Vries BB, Shendure J, Verloes A, Veltman JA, Brunner HG, Ross ME, Pilz DT, Dobyns WB

Abstract

Brain malformations are individually rare but collectively common causes of developmental disabilities. Many forms of malformation occur sporadically and are associated with reduced reproductive fitness, pointing to a causative role for de novo mutations. Here, we report a study of Baraitser-Winter syndrome, a well-defined disorder characterized by distinct craniofacial features, ocular colobomata and neuronal migration defect. Using whole-exome sequencing of three proband-parent trios, we identified de novo missense changes in the cytoplasmic actin-encoding genes ACTB and ACTG1 in one and two probands, respectively. Sequencing of both genes in 15 additional affected individuals identified disease-causing mutations in all probands, including two recurrent de novo alterations (ACTB, encoding p.Arg196His, and ACTG1, encoding p.Ser155Phe). Our results confirm that trio-based exome sequencing is a powerful approach to discover genes causing sporadic developmental disorders, emphasize the overlapping roles of cytoplasmic actin proteins in development and suggest that Baraitser-Winter syndrome is the predominant phenotype associated with mutation of these two genes.

MeSH Terms
Abnormalities, Multiple/genetics Actins/genetics Adolescent Adult Amino Acid Sequence Base Sequence Brain/abnormalities Child Coloboma/genetics DNA Copy Number Variations Developmental Disabilities/genetics Female Humans Intellectual Disability/genetics Male Molecular Sequence Data Mutation, Missense Nervous System Malformations/genetics PAX9 Transcription Factor/genetics Sequence Alignment Sequence Analysis, DNA Sequence Deletion Syndrome
Chemicals
Actins PAX9 Transcription Factor PAX9 protein, human
Authors & Affiliations
33 authors, click to expand affiliations / ORCID
Rivière Jean-Baptiste
Center for Integrative Brain Research, Seattle Children's Hospital, Seattle, Washington, USA.
van Bon Bregje W M
Hoischen Alexander
Kholmanskikh Stanislav S
O'Roak Brian J
Gilissen Christian
Gijsen Sabine
Sullivan Christopher T
Christian Susan L
Abdul-Rahman Omar A
Atkin Joan F
Chassaing Nicolas
Drouin-Garraud Valerie
Fry Andrew E
Fryns Jean-Pierre
Gripp Karen W
Kempers Marlies
Kleefstra Tjitske
Mancini Grazia M S
Nowaczyk Małgorzata J M
van Ravenswaaij-Arts Conny M A
Roscioli Tony
Marble Michael
Rosenfeld Jill A
Siu Victoria M
de Vries Bert B A
Shendure Jay
Verloes Alain
Veltman Joris A
Brunner Han G
Ross M Elizabeth
Pilz Daniela T
Dobyns William B
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Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.1091
Published
2012-02-26
Epub
2012-00-26
Pages
440-4, S1-2
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC3677859
Subset
IM
Grants
NHLBI NIH HHS · RC2 HL102926 · United States
CIHR · Canada
NHLBI NIH HHS · HL-102924 · United States
NHLBI NIH HHS · RC2 HL102924 · United States
NINDS NIH HHS · NS058721 · United States
NHLBI NIH HHS · HL-102925 · United States
NHLBI NIH HHS · RC2 HL103010 · United States
NHLBI NIH HHS · HL-102923 · United States
NINDS NIH HHS · R01 NS058721 · United States
NHLBI NIH HHS · RC2 HL102923 · United States
NHLBI NIH HHS · UC2 HL102926 · United States
NHLBI NIH HHS · UC2 HL103010 · United States
NHLBI NIH HHS · HL-103010 · United States
NINDS NIH HHS · NS048120 · United States
NINDS NIH HHS · P01 NS048120 · United States
NHLBI NIH HHS · HL-102926 · United States
NIEHS NIH HHS · HHSN273200800010C · United States
NHLBI NIH HHS · UC2 HL102923 · United States
NHLBI NIH HHS · UC2 HL102924 · United States
NHLBI NIH HHS · RC2 HL102925 · United States
NHLBI NIH HHS · UC2 HL102925 · United States
External Links
PubMed source DOI: 10.1038/ng.1091 PMC Full Text View journal details
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