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Heterozygous Pathogenic Variant in DACT1 Causes an Autosomal‐Dominant Syndrome with Features Overlapping Townes–Brocks Syndrome
Author(s) -
Webb Bryn D.,
Metikala Sanjeeva,
Wheeler Patricia G.,
Sherpa Mingma D.,
Houten Sander M.,
Horb Marko E.,
Schadt Eric E.
Publication year - 2017
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23171
Subject(s) - biology , genetics
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.