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

Nat Med. 2020 Jan;26(1):98-109. doi: 10.1038/s41591-019-0705-y. Epub 2020 Jan 13.


Discovery of genotype-phenotype relationships remains a major challenge in clinical medicine. Here, we combined three sources of phenotypic data to uncover a new mechanism for rare and common diseases resulting from collagen secretion deficits. Using a zebrafish genetic screen, we identified the ric1 gene as being 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 identified individuals homozygous-by-descent for a rare variant in RIC1 and, through a guided clinical re-evaluation, it was discovered that they share signs with the BioVU-associated phenome. We named this new Mendelian syndrome CATIFA (cleft lip, cataract, tooth abnormality, intellectual disability, facial dysmorphism, attention-deficit hyperactivity disorder) and revealed further disease mechanisms. This gene-based, PheWAS-guided approach can accelerate the discovery of clinically relevant disease phenome and associated biological mechanisms.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / pathology*
  • Animals
  • Behavior, Animal
  • Biological Specimen Banks*
  • Chondrocytes / pathology
  • Chondrocytes / ultrastructure
  • Disease Models, Animal
  • Extracellular Matrix / metabolism
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Fibroblasts / ultrastructure
  • Guanine Nucleotide Exchange Factors / genetics*
  • Humans
  • Models, Biological
  • Musculoskeletal System / pathology
  • Osteogenesis
  • Phenomics*
  • Phenotype
  • Procollagen / metabolism
  • Protein Transport
  • Secretory Pathway
  • Syndrome
  • Zebrafish
  • Zebrafish Proteins / genetics*


  • Guanine Nucleotide Exchange Factors
  • Procollagen
  • RIC1 protein, human
  • Ric1 protein, zebrafish
  • Zebrafish Proteins