DACT1 – Townes-Brocks Syndrome

Townes-Brocks syndrome (TBS) is an autosomal-dominant disorder characterized by anal, ear, renal and limb malformations. While SALL1 is a canonical TBS gene, emerging data implicate DACT1 in a syndromic phenotype overlapping TBS. DACT1 encodes a Wnt signaling antagonist critical for organogenesis, and pathogenic variants in this gene have been observed in multiple families with imperforate anus, external ear anomalies, and kidney defects.

In an initial report, a heterozygous DACT1 nonsense variant, c.1146G>A (p.Trp382Ter), was identified by whole-exome sequencing in a family presenting with imperforate anus, structural renal abnormalities and ear malformations consistent with TBS features. The variant segregated with disease across affected members in an autosomal-dominant pattern (1 family [PMID:28054444]).

Subsequently, targeted sequencing in a cohort of 209 families with congenital anomalies of the kidney and urinary tract (CAKUT) uncovered DACT1 missense variants in 8 unrelated families (3.8% vs. 1.7% in controls), all located in the DVL2-interaction region and predicted to be hypomorphic (8 families [PMID:36066768]). Carriers exhibited kidney agenesis, duplex or multicystic dysplasia with hydronephrosis, anal canal and spinal anomalies overlapping TBS2 features.

In total, DACT1 variants have been reported in 9 probands (1 family [PMID:28054444]; 8 families [PMID:36066768]) with an autosomal-dominant inheritance. The variant spectrum includes one truncating allele and multiple hypomorphic missense alleles. A representative allele is c.1146G>A (p.Trp382Ter).

Functional studies demonstrate that the p.Trp382Ter protein is stable in HEK293 cells and drives a proctodeum enlargement phenotype in Xenopus embryos, recapitulating anorectal malformations. Biochemical assays on hypomorphic missense variants reveal reduced DACT1–DVL2 binding and impaired branching morphogenesis in CRISPR/Cas9-edited murine collecting duct cells, confirming disruption of Wnt signaling in affected tissues ([PMID:28054444]; [PMID:36066768]).

Collectively, moderate clinical validity is supported by segregation in a familial case, replication across independent cohorts, and concordant functional data. Integration of genetic and experimental findings establishes DACT1 as a TBS locus with diagnostic utility in patients presenting with overlapping anal, ear and renal malformations. Key take-home: Heterozygous DACT1 variants cause a dominantly inherited TBS-like syndrome, warranting inclusion of DACT1 in diagnostic gene panels for Townes-Brocks and CAKUT phenotypes.

References

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

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