Date of Award

January 2019

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)



First Advisor

Silvia Vilarinho


Adult patients suffering from liver disease of unknown cause represent an understudied and underserved population. Over the past 15 years, next-generation sequencing technologies have matured into an inexpensive, effective, and widely available set of tools to do genomic analysis. One of these technologies, whole-exome sequencing (WES), allows for high throughput sequencing of all of the genome’s protein coding regions (exons). In pediatric cohorts, WES combined with deep clinical phenotyping has been shown to be an effective and unbiased method of identifying rare protein-altering coding variants in individual genes. WES has also contributed to the diagnosis and individualization of medical care in oncologic patients. The use of WES for the study of a broader spectrum of non-oncological diseases, among adults, remains poorly understood. We assessed the utility of WES in the diagnosis and management of adults with unexplained liver disease despite a comprehensive conventional workup and with no history of alcohol overuse.

We performed exome sequencing and deep phenotyping in two independent adult cohorts with unexplained liver disease. In the first cohort, we analyzed nineteen unrelated adult patients with idiopathic liver disease recruited at Yale New Haven Hospital. In a second cohort from Bridgeport Hospital, four unrelated adult patients presenting with fatty liver disease, hypertriglyceridemia, insulin resistance, and physical exam findings suggestive of lipodystrophy were recruited for genomic analysis.

In cohort 1, analysis of the exome in nineteen cases identified four monogenic disorders in five unrelated adults. Patient 1 suffered for 18 years from devastating complications of undiagnosed Type 3 Familial Partial Lipodystrophy due to a deleterious heterozygous variant in PPARG. Molecular diagnosis enabled initiation of leptin replacement therapy with subsequent normalization of liver transaminases, and amelioration of dyslipidemia. Patients 2 and 3 were diagnosed with MDR3 deficiency (also known as PFIC3, progressive intrahepatic familial cholestasis type 3) due to recessive mutations in ABCB4. Patient 4 with a prior diagnosis of non-alcoholic steatohepatitis was found to harbor a mitochondrial disorder due to a homozygous pathogenic variant in NDUFB3; subsequent muscle biopsy revealed a deficiency of rotenone sensitive I+III activity consistent with a mitochondrial disorder. This finding enabled initiation of disease-preventative measures including supplementation with antioxidants. Patient 5 is a lean patient with hepatic steatosis of unknown etiology who was found to have a damaging heterozygous variant in APOB, consistent with familial hypobetalipoproteinemia. In cohort 2, we identified a potential genetic diagnosis in all four cases of suspected lipodystrophy, including a patient with an LMNA mutation, a patient with two pathogenic heterozygous mutations in APOE, a patient with a homozygous deleterious mutation in the leptin receptor (LEPR), and a patient with a pathogenic heterozygous variant in PPARG.

In conclusion, WES provided a diagnosis with impact on clinical management in a significant number of adults suffering from liver disease of unknown cause, gaining insight into disease pathogenesis and identifying new therapeutic and preventive medicine interventions. This study supports the use of WES in the evaluation and management of adults with idiopathic liver disease in clinical practice.


This is an Open Access Thesis.

Open Access

This Article is Open Access