Although over 50 genes are known to cause renal malformation if mutated, the underlying genetic basis, most easily identified in syndromic cases, remains unsolved in most patients. 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 GDF6 gene encoding growth differentiation factor 6, a member of the BMP family of ligands. Previously, GDF6 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 GDF6 in the pathogenesis of renal malformation, we performed targeted sequencing in 193 further patients identifying rare GDF6 variants in two cases with kidney hypodysplasia and extrarenal manifestations. During development, gdf6 was expressed in the pronephric tubule of Xenopus laevis, and Gdf6 expression was observed in the ureteric tree of the murine kidney by RNA in situ hybridization. CRISPR/Cas9-derived knockout of Gdf6 attenuated migration of murine IMCD3 cells, an effect rescued by expression of wild-type but not mutant GDF6, indicating affected variant function regarding a fundamental developmental process. Knockdown of gdf6 in Xenopus laevis resulted in impaired pronephros development. Altogether, we identified rare heterozygous GDF6 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 GDF6 variant carriers and suggesting an involvement of GDF6 in nephrogenesis.

Department of Human Genetics Hannover Medical School 30625 Hannover Germany

Department of Medicine Renal Division University Medical Center Freiburg Faculty of Medicine University of Freiburg 79110 Freiburg Germany

Department of Neuropathology Institute of Pathology Hannover Medical School 30625 Hannover Germany

Department of Paediatrics and Transplantation Center University Hospital Motol 2nd Faculty of Medicine Charles University 150 06 Prague Czech Republic

Department of Pediatric Kidney Liver and Metabolic Diseases Hannover Medical School 30625 Hannover Germany

Division of Paediatric and Adolescent Medicine Oslo University Hospital 0424 Oslo Norway

Genome Analytics Research Group Helmholtz Centre for Infection Research 38124 Braunschweig Germany

Institute of Anatomy and Zurich Center for Integrative Human Physiology University of Zurich 8057 Zurich Switzerland

Institute of Molecular Biology Hannover Medical School 30625 Hannover Germany

Medical Faculty Skopje University Children's Hospital 1000 Skopje North Macedonia

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