2. Academic Validation
  3. Heterozygous Pathogenic Variant in DACT1 Causes an Autosomal-Dominant Syndrome with Features Overlapping Townes-Brocks Syndrome

Heterozygous Pathogenic Variant in DACT1 Causes an Autosomal-Dominant Syndrome with Features Overlapping Townes-Brocks Syndrome

  • Hum Mutat. 2017 Apr;38(4):373-377. doi: 10.1002/humu.23171.
Bryn D Webb 1 2 3,  Sanjeeva Metikala 4,  Patricia G Wheeler 5,  Mingma D Sherpa 1,  Sander M Houten 1 3,  Marko E Horb 4,  Eric E Schadt 1 3
Affiliations

Affiliations

  • 1 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
  • 2 Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York.
  • 3 Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York.
  • 4 Bell Center for Regenerative Biology and Tissue Engineering and National Xenopus Resource, Marine Biological Laboratory, Woods Hole, Massachusetts.
  • 5 Department of Pediatrics, Division of Genetics, Nemours Children's Clinic, Orlando, Florida.
PMID: 28054444 DOI: 10.1002/humu.23171
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.

Keywords

DACT1; Townes-Brocks syndrome; genitourinary anomaly; imperforate anus; microtia; renal malformation.

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