De novo missense variants in WDR37 cause a severe ocular syndrome

Abstract

AbstractUsing exome sequencing we have discovered de novo missense variants in WDR37 in unrelated patients with a complex phenotype, which we named WDR37 syndrome. Patients with this syndrome demonstrated corneal opacity, coloboma and microcornea, dysmorphic facial features, significant neurological impairment with structural brain defects and seizure onset shortly after birth, poor feeding, and variable skeletal, cardiac, genitourinary defects and early lethality in one. WDR37 encodes a protein of unknown function with seven predicted WD40 domains. We undertook further functional characterization of the gene and variants in human cell lines and zebrafish. Immunocytochemistry and Western blot studies revealed that wild‐type WDR37 is predominantly localized in the cytoplasm and mutant proteins showed similar expression levels and localization. CRISPR‐Cas9 mediated genome editing generated zebrafish mutants with missense and frameshift variants, including one that replicated a human variant. Zebrafish carrying heterozygous missense mutations demonstrated larval lethality, while embryos with frameshift alleles survived to adulthood, suggesting a dominant negative mechanism for the human missense variants. Analysis of RNAseq data from mutant zebrafish embryos revealed significant upregulation of cholesterol biosynthesis pathways. Additional studies into possible function of this important factor and disease mechanisms are ongoing. In summary, we report a novel human disease gene with an essential role in vertebrate development and provide the first insight into its possible role.