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

Unlu G, Qi X, Gamazon ER, Melville DB, Patel N, Rushing AR, Hashem M, Al-Faifi A, Chen R, Li B, Cox NJ, Alkuraya FS, Knapik EW
Nat Med. 2020 26 (1): 98-109

PMID: 31932796 · PMCID: PMC7147997 · DOI:10.1038/s41591-019-0705-y

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.

MeSH Terms (21)

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

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