PUBLICATION
Phenome-based approach identifies RIC1-linked Mendelian syndrome through zebrafish models, biobank associations and clinical studies
- Authors
- Unlu, G., Qi, X., Gamazon, E.R., Melville, D.B., Patel, N., Rushing, A.R., Hashem, M., Al-Faifi, A., Chen, R., Li, B., Cox, N.J., Alkuraya, F.S., Knapik, E.W.
- ID
- ZDB-PUB-200115-5
- Date
- 2020
- Source
- Nature medicine 26: 98-109 (Journal)
- Registered Authors
- Knapik, Ela W., Melville, David, Rushing, Amy Rene, Unlu, Gokhan
- Keywords
- none
- 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*
- PubMed
- 31932796 Full text @ Nat. Med.
Citation
Unlu, G., Qi, X., Gamazon, E.R., Melville, D.B., Patel, N., Rushing, A.R., Hashem, M., Al-Faifi, A., Chen, R., Li, B., Cox, N.J., Alkuraya, F.S., Knapik, E.W. (2020) Phenome-based approach identifies RIC1-linked Mendelian syndrome through zebrafish models, biobank associations and clinical studies. Nature medicine. 26:98-109.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping