title: De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome.
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.
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Hospital, Seattle, Washington, USA.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Rivière
authors.forename: Bregje W M
authors.initials: BW
authors.lastname: van Bon
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.forename: Stanislav S
authors.initials: SS
authors.lastname: Kholmanskikh
authors.forename: Brian J
authors.initials: BJ
authors.lastname: O'Roak
authors.forename: Christian
authors.initials: C
authors.lastname: Gilissen
authors.forename: Sabine
authors.initials: S
authors.lastname: Gijsen
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Sullivan
authors.forename: Susan L
authors.initials: SL
authors.lastname: Christian
authors.forename: Omar A
authors.initials: OA
authors.lastname: Abdul-Rahman
authors.forename: Joan F
authors.initials: JF
authors.lastname: Atkin
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chassaing
authors.forename: Valerie
authors.initials: V
authors.lastname: Drouin-Garraud
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Fry
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Fryns
authors.forename: Karen W
authors.initials: KW
authors.lastname: Gripp
authors.forename: Marlies
authors.initials: M
authors.lastname: Kempers
authors.forename: Tjitske
authors.initials: T
authors.lastname: Kleefstra
authors.forename: Grazia M S
authors.initials: GM
authors.lastname: Mancini
authors.forename: Małgorzata J M
authors.initials: MJ
authors.lastname: Nowaczyk
authors.forename: Conny M A
authors.initials: CM
authors.lastname: van Ravenswaaij-Arts
authors.forename: Tony
authors.initials: T
authors.lastname: Roscioli
authors.forename: Michael
authors.initials: M
authors.lastname: Marble
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Siu
authors.forename: Bert B A
authors.initials: BB
authors.lastname: de Vries
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.forename: Alain
authors.initials: A
authors.lastname: Verloes
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.forename: M Elizabeth
authors.initials: ME
authors.lastname: Ross
authors.forename: Daniela T
authors.initials: DT
authors.lastname: Pilz
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000199:Actins / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D001921:Brain / Q000002:abnormalities*; D002648:Child; D003103:Coloboma / Q000235:genetics; D056915:DNA Copy Number Variations; D002658:Developmental Disabilities / Q000235:genetics; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009421:Nervous System Malformations / Q000235:genetics; D051764:PAX9 Transcription Factor / Q000235:genetics; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D013577:Syndrome
chemical_list: D000199:Actins; D051764:PAX9 Transcription Factor; C497323:PAX9 protein, human