title: Heterozygous Pathogenic Variant in DACT1 Causes an Autosomal-Dominant Syndrome with Features Overlapping Townes-Brocks Syndrome.
abstract: A heterozygous nonsense variant was identified in dapper, antagonist of beta-catenin, 1 (DACT1) via whole-exome sequencing in family members with imperforate anus, structural renal abnormalities, genitourinary anomalies, and/or ear anomalies. The DACT1 c.1256G>A;p.Trp419*variant segregated appropriately in the family consistent with an autosomal dominant mode of inheritance. DACT1 is a member of the Wnt-signaling pathway, and mice homozygous for null alleles display multiple congenital anomalies including absent anus with blind-ending colon and genitourinary malformations. To investigate the DACT1 c.1256G>A variant, HEK293 cells were transfected with mutant DACT1 cDNA plasmid, and immunoblotting revealed stability of the DACT1 p.Trp419*protein. Overexpression of DACT1 c.1256G>A mRNA in Xenopus embryos revealed a specific gastrointestinal phenotype of enlargement of the proctodeum. Together, these findings suggest that the DACT1 c.1256G>A nonsense variant is causative of a specific genetic syndrome with features overlapping Townes-Brocks syndrome.
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.|Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York.|Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Bryn D
authors.initials: BD
authors.lastname: Webb
authors.affiliation: Bell Center for Regenerative Biology and Tissue Engineering and National Xenopus Resource, Marine Biological Laboratory, Woods Hole, Massachusetts.
authors.forename: Sanjeeva
authors.initials: S
authors.lastname: Metikala
authors.affiliation: Department of Pediatrics, Division of Genetics, Nemours Children's Clinic, Orlando, Florida.
authors.forename: Patricia G
authors.initials: PG
authors.lastname: Wheeler
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Mingma D
authors.initials: MD
authors.lastname: Sherpa
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.|Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Sander M
authors.initials: SM
authors.lastname: Houten
authors.affiliation: Bell Center for Regenerative Biology and Tissue Engineering and National Xenopus Resource, Marine Biological Laboratory, Woods Hole, Massachusetts.
authors.forename: Marko E
authors.initials: ME
authors.lastname: Horb
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.|Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D001006:Anus, Imperforate; D018389:Codon, Nonsense; D005799:Genes, Dominant; D057809:HEK293 Cells; D006319:Hearing Loss, Sensorineural; D006579:Heterozygote; D006801:Humans; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods; D013577:Syndrome; D013933:Thumb / Q000002:abnormalities*; D014564:Urogenital Abnormalities; D014981:Xenopus
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018389:Codon, Nonsense; C491683:DACT1 protein, human; D009687:Nuclear Proteins
keywords: DACT1; Townes-Brocks syndrome; genitourinary anomaly; imperforate anus; microtia; renal malformation