Phenome-based approach identifies RIC1-linked Mendelian syndrome through zebrafish models, biobank associations, and clinical studies

Discovery of genotype-phenotype relationships remains a major challenge in clinical medicine. Here, we combined three sources of phenotypic data to uncover a novel mechanism for rare and common diseases resulting from collagen secretion deficits. Using zebrafish genetic screen, we identified the ric1 gene to be essential for skeletal biology. Using a gene-based phenome-wide association study (PheWAS) in the EHR-linked BioVU biobank, we show that reduced genetically determined expression of RIC1 is associated with musculoskeletal and dental conditions. Whole exome sequencing (WES) identified individuals homozygous-by-descent for a rare variant in RIC1, and, through a guided clinical re-evaluation, they were discovered to share signs with the BioVU-associated phenome. We named this novel Mendelian syndrome CATIFA (Cleft lip, cAtaract, Tooth abnormality, Intellectual disability, Facial dysmorphism, ADHD), and revealed further disease mechanisms. This gene-based PheWAS-guided approach can accelerate the discovery of clinically relevant disease phenome and associated biological mechanisms.