Date of Award

January 2020

Document Type


Degree Name

Medical Doctor (MD)



First Advisor

Silvia Vilarinho


BACKGROUND: Much of our understanding of normal liver pathophysiology comes from studying patients with liver disease who remain undiagnosed after a comprehensive workup. Searching for diagnoses among such cohorts has benefits both for the underserved patients with idiopathic liver disease, but also for science as a whole. Unbiased genomic analysis of patients with undiagnosed disease has yielded remarkable results, including clinically actionable diagnoses in children and adults, as well as the discovery of novel genetic diseases. Thus, we posit that among pediatric patients with undiagnosed liver disease, there may be previously unrecognized Mendelian causes.

METHODS: We report a 2.5 year old with unexplained congenital chronic diarrhea, coagulopathy, fat-soluble vitamin deficiency, cholestasis and liver fibrosis. Exome sequencing and analysis was performed. Once a gene of interest was revealed, its expression at the mRNA level was assessed in colon tissue biopsy of the proband.

RESULTS: Exome sequencing uncovered a previously unidentified homozygous premature termination mutation (p.Gln186*) in SLC51A, encoding for the alpha subunit of the heteromeric organic solute transporter alpha-beta (OSTα-β), an important contributor to intestinal bile acid reabsorption in the enterohepatic circulation. Gene expression assay showed absence of SLC51A and detectable SLC51B mRNA transcripts in the proband’s colon tissue.

CONCLUSION: This study identifies a novel genetic digestive disorder due to OSTα deficiency. Homozygous loss-of-function mutation in SLC51A causes chronic diarrhea, features of cholestasis, and liver fibrosis. Our findings further contribute to the body of evidence showing the importance of studying patients with undiagnosed disease, and the utility of whole exome sequencing as a powerful tool in clinical diagnosis and scientific discovery.


This thesis is restricted to Yale network users only. It will be made publicly available on 09/10/2022