Variants in cause a novel oculo-vertebral-renal (OVR) syndrome.

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 in these families. We performed in silico, cellular and zebrafish experiments to demonstrate the variants were pathogenic or likely pathogenic for OVR syndrome. Knockdown of either or both zebrafish paralogs of results in abnormal eye and somite development, which was rescued by wild-type but not variant mRNA. Illustrating the power of genomic ascertainment in medicine, our study establishes as a critical factor in eye and vertebral development and a pleiotropic gene responsible for OVR syndrome.