Phenome-based approach identifies RIC1-linked Mendelian syndrome through zebrafish models, biobank associations and clinical studies.
Gokhan UnluXinzi QiEric R GamazonDavid B MelvilleNisha PatelAmy R RushingMais HashemAbdullah Al-FaifiRui ChenBingshan LiNancy J CoxFowzan Sami AlkurayaEla W KnapikPublished in: Nature medicine (2020)
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.
Keyphrases
- attention deficit hyperactivity disorder
- genome wide
- intellectual disability
- autism spectrum disorder
- copy number
- high throughput
- small molecule
- genome wide identification
- dna methylation
- electronic health record
- poor prognosis
- case report
- drinking water
- single cell
- working memory
- transcription factor
- big data
- genome wide analysis