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In search of novel causative genes, whole-exome sequencing in a patient with renal, i.e., crossed fused renal ectopia, and extrarenal, i.e., skeletal, eye, and ear, malformations yielded a rare heterozygous variant in the <jats:italic>GDF6<\/jats:italic> gene encoding growth differentiation factor 6, a member of the BMP family of ligands. Previously, <jats:italic>GDF6<\/jats:italic> variants were reported to cause pleiotropic defects including skeletal, e.g., vertebral, carpal, tarsal fusions, and ocular, e.g., microphthalmia and coloboma, phenotypes. To assess the role of <jats:italic>GDF6<\/jats:italic> in the pathogenesis of renal malformation, we performed targeted sequencing in 193 further patients identifying rare <jats:italic>GDF6<\/jats:italic> variants in two cases with kidney hypodysplasia and extrarenal manifestations. During development, <jats:italic>gdf6<\/jats:italic> was expressed in the pronephric tubule of <jats:italic>Xenopus laevis<\/jats:italic>, and <jats:italic>Gdf6<\/jats:italic> expression was observed in the ureteric tree of the murine kidney by RNA in situ hybridization. CRISPR\/Cas9-derived knockout of <jats:italic>Gdf6<\/jats:italic> attenuated migration of murine IMCD3 cells, an effect rescued by expression of wild-type but not mutant <jats:italic>GDF6<\/jats:italic>, indicating affected variant function regarding a fundamental developmental process. Knockdown of <jats:italic>gdf6<\/jats:italic> in <jats:italic>Xenopus laevis<\/jats:italic> resulted in impaired pronephros development. Altogether, we identified rare heterozygous <jats:italic>GDF6<\/jats:italic> variants in 1.6% of all renal anomaly patients and 5.4% of renal anomaly patients additionally manifesting skeletal, ocular, or auricular abnormalities, adding renal hypodysplasia and fusion to the phenotype spectrum of <jats:italic>GDF6<\/jats:italic> variant carriers and suggesting an involvement of GDF6 in nephrogenesis.<\/jats:p>","DOI":"10.1038\/s41431-020-0678-9","type":"journal-article","created":{"date-parts":[[2020,7,31]],"date-time":"2020-07-31T12:04:11Z","timestamp":1596197051000},"page":"1681-1693","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Rare heterozygous GDF6 variants in patients with renal anomalies"],"prefix":"10.1038","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7294-3476","authenticated-orcid":false,"given":"Helge","family":"Martens","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imke","family":"Hennies","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maike","family":"Getwan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Christians","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna-Carina","family":"Weiss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Brand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann Christin","family":"Gjerstad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arne","family":"Christians","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoran","family":"Gucev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Geffers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom\u00e1\u0161","family":"Seeman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Kispert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3377-1245","authenticated-orcid":false,"given":"Velibor","family":"Tasic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Bjerre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soeren S.","family":"Lienkamp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9601-7813","authenticated-orcid":false,"given":"Dieter","family":"Haffner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6610-1080","authenticated-orcid":false,"given":"Ruthild G.","family":"Weber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,7,31]]},"reference":[{"key":"678_CR1","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1007\/s00404-001-0265-4","volume":"266","author":"A Queisser-Luft","year":"2002","unstructured":"Queisser-Luft A, Stolz G, Wiesel A, Schlaefer K, Spranger J. 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