Date of Award

January 2022

Document Type


Degree Name

Medical Doctor (MD)



First Advisor

Silvia Vilarinho


While in recent years whole exome sequencing (WES) has been used increasingly in clinical care, it remains underutilized for adults with non-oncological disorders. A significant barrier to genomic medicine’s application in adult hepatology is the belief that genetic defects are uncommon in the presentation of adult disease. However, we have previously demonstrated in a pilot study the clinical utility of genome analysis in the diagnosis and management of adults with idiopathic liver disease. Thus, we hypothesize that the incorporation of genomic analysis in the evaluation of patients with unexplained liver disease will improve diagnosis and provide excellent patient care. We aim (1) to validate the clinical utility of WES in a larger, multi-center cohort of patients with liver dysfunction of unknown etiology and (2) to launch an educational, multidisciplinary hepatology genome rounds series discussing patient cases in which diagnosis and/or management were informed by WES results. In Aim 1, we employed WES analysis paired with deep clinical phenotyping to a cohort of 59 adults with liver disease of uncertain etiology despite a comprehensive work-up. WES analysis comprised of evaluation for single nucleotide variants and copy number variants (CNVs) across the entire exome. WES analysis revealed a definitive or very likely genetic diagnoses in 14 patients, illuminating the root cause of their liver disease and enhanced optimal medical care. These patients harbor rare, predicted-to-be deleterious mutations in a variety of different genes, including ABCB4, APOB, RTEL1, DYSF, ABCB11, ABHD5, SMAD3, SCARB1, LIPE and JAG1; additionally, one patient was found to have a monoallelic 17q12 deletion detected by CNV analysis. The clinical utility of WES was validated in our adult idiopathic liver disease cohort with a diagnostic rate of ~25%. In Aim 2, we developed the inaugural multidisciplinary Hepatology Genome Rounds series to discuss and incorporate genetic information in clinical care. This pilot series ran in a virtual format every three months from March 2021 to December 2021, featuring four different patient cases with distinct learning objectives and discussions led by a multidisciplinary team of hepatology, medical genetics, and pathology experts. Collectively, our findings not only impact individual patient care directly, but also fuel the disseminated utilization of genomic medicine and ultimately refine our understanding and clinical care of liver disease.


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