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. ela.knapik@vumc.org.
11 Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA. ela.knapik@vumc.org.
12 Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA. ela.knapik@vumc.org.
# 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.

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