Date of Award

January 2026

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Silvia Vilarinho

Abstract

Chronic liver disease affects approximately 1.7 billion people worldwide, yet a substantial proportion of patients remain undiagnosed. As next-generation sequencing technologies have advanced, an increasing number of genetic causes of liver disease have been identified. Although these conditions have historically been recognized in childhood, growing evidence indicates that genetic factors play an important role in adults with idiopathic liver disease. Prior work from our group and others has demonstrated that whole-exome sequencing (WES) can establish a molecular diagnosis in approximately 25% of patients with otherwise unexplained liver disease, with cholestasis emerging as a particularly high-yield phenotype.In this study, we sought to define the diagnostic yield of genetic evaluation in adults with unexplained cholestatic liver disease and to characterize the clinical phenotypes associated with genetic diagnoses made in adulthood. We performed WES on 31 adults recruited from two academic centers following an unrevealing conventional diagnostic workup. Pathogenic or likely pathogenic variants were identified in 10 patients (32%). ABCB4 was the most frequently implicated gene, accounting for 8 of 10 genetic diagnoses. Diagnostic yield was not associated with gender or family history of liver disease; however, younger age at presentation (<40 years) was significantly associated with identification of a genetic diagnosis. Despite the relatively small cohort size, our findings highlight several important clinical challenges, including phenotypic heterogeneity, misdiagnosis, and delayed recognition of genetic liver disease. They also demonstrate the clinical benefits of establishing a genetic diagnosis, such as improved prognostication and management and family counseling. Collectively, these results underscore the limitations of phenotype-driven testing alone and support the use of comprehensive genomic approaches to improve diagnosis and clinical management in adults with unexplained cholestatic liver disease.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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