DACT1 – Townes-Brocks syndrome 2

Heterozygous variants in DACT1 have been implicated in Townes-Brocks syndrome 2 (TBS2), an autosomal dominant disorder characterized by imperforate anus, renal anomalies, ear malformations, and skeletal defects. Initial evidence arose from a multigenerational family harboring a nonsense DACT1 variant segregating with imperforate anus, structural renal anomalies, and ear malformations consistent with TBS2 (PMID:28054444). More recently, eight additional unrelated probands presenting with renal agenesis, anorectal anomalies, and TBS2-like features were found to carry very rare missense variants in the DVL2 interaction domain of DACT1 (PMID:36066768).

Genetic analyses across nine unrelated probands revealed eight distinct missense and one recurrent nonsense variant in DACT1, all fitting an autosomal dominant inheritance pattern with exclusive maternal transmission in the CAKUT cohort. Segregation analysis in the original 2017 family demonstrated co-segregation of p.Trp382Ter with disease in four affected relatives (PMID:28054444). Variant spectrum includes eight missense changes and one recurrent p.Trp382Ter nonsense allele, with no observed founder effect. Representative variant: c.1660C>T (p.Leu554Phe) (PMID:36066768).

Functional studies support a hypomorphic mechanism of pathogenicity. Biochemical assays showed that DACT1 missense alleles reduce binding to DVL2, perturbing Wnt/β-catenin signaling. In vitro branching morphogenesis assays using CRISPR/Cas9 Dact1−/− murine collecting duct cells recapitulated impaired tubule formation. Murine expression profiling confirmed Dact1 expression in developing kidney, anal canal, vertebrae, and brain, matching the human phenotype (PMID:36066768). Overexpression of the p.Trp382Ter allele in Xenopus embryos induced anal dysgenesis, and HEK293 assays demonstrated stability of the truncated protein, suggesting a dominant-negative or haploinsufficient effect (PMID:28054444).

No conflicting evidence has been reported for DACT1 in TBS2, and all functional and segregation data align to support the gene-disease relationship. The combined genetic and experimental findings meet ClinGen criteria for a Strong gene–disease association.

Key take-home: Heterozygous hypomorphic DACT1 variants cause autosomal dominant Townes-Brocks syndrome 2, and genetic testing of DACT1 should be considered in patients with overlapping anorectal and renal anomalies.

References

• Human genetics • 2023 • Heterozygous variants in the DVL2 interaction region of DACT1 cause CAKUT and features of Townes-Brocks syndrome 2. PMID:36066768
• Human mutation • 2017 • Heterozygous Pathogenic Variant in DACT1 Causes an Autosomal-Dominant Syndrome with Features Overlapping Townes-Brocks Syndrome. PMID:28054444

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