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In search of novel genes associated with CAKUT in humans, we applied whole-exome sequencing in a patient with kidney, anorectal, spinal, and brain anomalies, and identified a rare heterozygous missense variant in the <jats:italic>DACT1<\/jats:italic> (dishevelled binding antagonist of beta catenin 1) gene encoding a cytoplasmic WNT signaling mediator. Our patient\u2019s features overlapped Townes\u2013Brocks syndrome 2 (TBS2) previously described in a family carrying a <jats:italic>DACT1<\/jats:italic> nonsense variant as well as those of <jats:italic>Dact1<\/jats:italic>-deficient mice. Therefore, we assessed the role of <jats:italic>DACT1<\/jats:italic> in CAKUT pathogenesis. Taken together, very rare (minor allele frequency\u2009\u2264\u20090.0005) non-silent <jats:italic>DACT1<\/jats:italic> variants were detected in eight of 209 (3.8%) CAKUT families, significantly more frequently than in controls (1.7%). All seven different <jats:italic>DACT1<\/jats:italic> missense variants, predominantly likely pathogenic and exclusively maternally inherited, were located in the interaction region with DVL2 (dishevelled segment polarity protein 2), and biochemical characterization revealed reduced binding of mutant DACT1 to DVL2. Patients carrying <jats:italic>DACT1<\/jats:italic> variants presented with kidney agenesis, duplex or (multi)cystic (hypo)dysplastic kidneys with hydronephrosis and TBS2 features. During murine development, <jats:italic>Dact1<\/jats:italic> was expressed in organs affected by anomalies in patients with <jats:italic>DACT1<\/jats:italic> variants, including the kidney, anal canal, vertebrae, and brain. In a branching morphogenesis assay, tubule formation was impaired in CRISPR\/Cas9-induced <jats:italic>Dact1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> murine inner medullary collecting duct cells. In summary, we provide evidence that heterozygous hypomorphic <jats:italic>DACT1<\/jats:italic> variants cause CAKUT and other features of TBS2, including anomalies of the skeleton, brain, distal digestive and genital tract.<\/jats:p>","DOI":"10.1007\/s00439-022-02481-6","type":"journal-article","created":{"date-parts":[[2022,9,6]],"date-time":"2022-09-06T05:03:41Z","timestamp":1662440621000},"page":"73-88","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Heterozygous variants in the DVL2 interaction region of DACT1 cause CAKUT and features of Townes\u2013Brocks syndrome 2"],"prefix":"10.1007","volume":"142","author":[{"given":"Anne","family":"Christians","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Esra","family":"Kesdiren","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Imke","family":"Hennies","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alejandro","family":"Hofmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark-Oliver","family":"Trowe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5537-8543","authenticated-orcid":false,"given":"Frank","family":"Brand","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7294-3476","authenticated-orcid":false,"given":"Helge","family":"Martens","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ann Christin","family":"Gjerstad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zoran","family":"Gucev","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias","family":"Zirngibl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Geffers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tom\u00e1\u0161","family":"Seeman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heiko","family":"Billing","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Bjerre","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Velibor","family":"Tasic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Kispert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benno","family":"Ure","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dieter","family":"Haffner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jens","family":"Dingemann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6610-1080","authenticated-orcid":false,"given":"Ruthild G.","family":"Weber","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,9,6]]},"reference":[{"key":"2481_CR1","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1534\/genetics.117.1125","volume":"207","author":"PD Brophy","year":"2017","unstructured":"Brophy PD, Rasmussen M, Parida M et al (2017) A gene implicated in activation of retinoic acid receptor targets is a novel renal agenesis gene in humans. 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