title: Exome sequencing identifies a recurrent de novo ZSWIM6 mutation associated with acromelic frontonasal dysostosis.
abstract: Acromelic frontonasal dysostosis (AFND) is a rare disorder characterized by distinct craniofacial, brain, and limb malformations, including frontonasal dysplasia, interhemispheric lipoma, agenesis of the corpus callosum, tibial hemimelia, preaxial polydactyly of the feet, and intellectual disability. Exome sequencing of one trio and two unrelated probands revealed the same heterozygous variant (c.3487C>T [p. Arg1163Trp]) in a highly conserved protein domain of ZSWIM6; this variant has not been seen in the 1000 Genomes data, dbSNP, or the Exome Sequencing Project. Sanger validation of the three trios confirmed that the variant was de novo and was also present in a fourth isolated proband. In situ hybridization of early zebrafish embryos at 24 hr postfertilization (hpf) demonstrated telencephalic expression of zswim6 and onset of midbrain, hindbrain, and retinal expression at 48 hpf. Immunohistochemistry of later-stage mouse embryos demonstrated tissue-specific expression in the derivatives of all three germ layers. qRT-PCR expression analysis of osteoblast and fibroblast cell lines available from two probands was suggestive of Hedgehog pathway activation, indicating that the ZSWIM6 mutation associated with AFND may lead to the craniofacial, brain and limb malformations through the disruption of Hedgehog signaling.
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Smith
authors.affiliation: Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, USA; Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Craniofacial Center, Seattle Children's Hospital, Seattle, WA 98105, USA.
authors.forename: Anne V
authors.initials: AV
authors.lastname: Hing
authors.affiliation: Craniofacial Center, Seattle Children's Hospital, Seattle, WA 98105, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Clarke
authors.affiliation: Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, USA.
authors.forename: Nathan M
authors.initials: NM
authors.lastname: Johnson
authors.affiliation: Department of Radiology, UW Medicine, Seattle, WA 98195, USA.
authors.forename: Francisco A
authors.initials: FA
authors.lastname: Perez
authors.affiliation: Craniofacial Center, Seattle Children's Hospital, Seattle, WA 98105, USA.
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Park
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Horst
authors.affiliation: Trialomics, Seattle, WA 98101, USA.
authors.forename: Brig
authors.initials: B
authors.lastname: Mecham
authors.affiliation: Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, USA; Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Maves
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.affiliation: Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, USA; Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Craniofacial Center, Seattle Children's Hospital, Seattle, WA 98105, USA. Electronic address: michael.cunningham@seattlechildrens.org.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Cunningham
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D019465:Craniofacial Abnormalities; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005145:Face / Q000002:abnormalities; D053823:Hedgehog Proteins / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability; D017880:Limb Deformities, Congenital / Q000235:genetics; D008342:Mandibulofacial Dysostosis / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D017434:Protein Structure, Tertiary / Q000235:genetics; D015027:Zebrafish; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D053823:Hedgehog Proteins; C000592373:ZSWIM6 protein, human
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