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.
Gokhan Unlu  1  2  3  4 ,  Xinzi Qi  1  2 ,  Eric R Gamazon  #  1  2  5 ,  David B Melville  #  1  6 ,  Nisha Patel  #  7 ,  Amy R Rushing  1  2 ,  Mais Hashem  7 ,  Abdullah Al-Faifi  8 ,  Rui Chen  2  9 ,  Bingshan Li  2  9 ,  Nancy J Cox  1  2 ,  Fowzan S Alkuraya  7 ,  Ela W Knapik  10  11  12
Affiliations
  • 1. Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 2. Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 3. Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA.
  • 4. Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, NY, USA.
  • 5. Clare Hall, University of Cambridge, Cambridge, UK.
  • 6. Department of Molecular and Cellular Biology, Howard Hughes Medical Institute, University of California, Berkeley, CA, USA.
  • 7. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
  • 8. Department of Pediatrics, Security Forces Hospital, Riyadh, Saudi Arabia.
  • 9. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
  • 10. Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. [email protected].
  • 11. Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA. [email protected].
  • 12. Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA. [email protected].
  • # Contributed equally.
PMID: 31932796 DOI: 10.1038/s41591-019-0705-y
Abstract

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.