Variants in NR6A1 as a cause for congenital renal, vertebral and uterine anomalies

The underlying cause for renal and uterine agenesis remains unknown in many cases, whereas recurrence in some families strongly suggests the involvement of genetic factors. Here, we identify 5 affected individuals from 3 families with phenotypes including bilateral or unilateral renal agenesis/hypoplasia, along with variable congenital uterine anomalies and costovertebral defects associated with heterozygous deleterious variants in NR6A1. The variant spectrum includes both inherited missense as well as de novo loss of function, with the latter associated with a perinatal lethal phenotype characterized by bilateral renal agenesis. In vitro studies demonstrated partial loss-of-function for both missense variants. To investigate the role of NR6A1 in development, CRISPR-Cas9 knockout zebrafish models targeting the orthologues nr6a1a and nr6a1b were generated. Mutants recapitulate the human phenotype, exhibiting impaired kidney development, including pronephros segmentation defects and adult kidney hypoplasia, along with axial skeletal abnormalities, cloacal anomalies, and disrupted anteroposterior expression of posterior hox genes. This study provides strong evidence linking NR6A1 heterozygous loss-of-function variants to renal, uterine and costovertebral defects in humans.