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

TitlePhenome-based approach identifies RIC1-linked Mendelian syndrome through zebrafish models, biobank associations and clinical studies.
Publication TypeJournal Article
Year of Publication2020
AuthorsUnlu, 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
JournalNat Med
Volume26
Issue1
Pagination98-109
Date Published2020 Jan
ISSN1546-170X
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.

DOI10.1038/s41591-019-0705-y
Alternate JournalNat. Med.
PubMed ID31932796
Grant ListR01MH113362 / / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) /
R01MH113362 / / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) /
15PRE22940041 / / American Heart Association (American Heart Association, Inc.) /
R35HG010718 / / U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI) /
U01HG009086 / / U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI) /
U01HG009086 / / U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI) /