Colobomatous microphthalmia is a potentially blinding congenital ocular malformation that can present either in isolation or together with other syndromic features. Despite a strong genetic component to disease, many cases lack a molecular diagnosis. We describe a novel autosomal dominant oculo-vertebral-renal (OVR) syndrome in six independent families characterized by colobomatous microphthalmia, missing vertebrae and congenital kidney abnormalities. Genome sequencing identified six rare variants in the orphan nuclear receptor gene NR6A1 in these families. We performed in silico, cellular and zebrafish experiments to demonstrate the NR6A1 variants were pathogenic or likely pathogenic for OVR syndrome. Knockdown of either or both zebrafish paralogs of NR6A1 results in abnormal eye and somite development, which was rescued by wild-type but not variant NR6A1 mRNA. Illustrating the power of genomic ascertainment in medicine, our study establishes NR6A1 as a critical factor in eye and vertebral development and a pleiotropic gene responsible for OVR syndrome.

The authors have declared no competing interest.

This study was supported by the Intramural Research Program of the NIH. GA is supported by a Fight For Sight (UK) Early Career Investigator Award (5045/46), the National Institute of Health Research Biomedical Research Centre (NIHR-BRC) at Moorfields Eye Hospital, and the UCL Institute of Ophthalmology, and Moorfields Eye Charity (Stephen and Elizabeth Archer in memory of Marion Woods) and NIH-P20GM139769. RY was supported by the Moorfields Eye Charity Career Development Award and Springboard (GR001155 and GR001210), Medical Research Council (MR/X001067/1) and FODNECYT (1221843). MIM was supported by Moorfields Eye Charity PhD Studentship (GR001661).

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