Clinical utility and genomic insights from whole exome and clinical exome sequencing in idiopathic liver disease

Abstract

Background: Chronic liver disease (CLD) is a major global health burden, causing ~ 2 million deaths annually. In a substantial proportion of cases, extensive hepatology and metabolic evaluations fail to determine the etiology, leading to classification as idiopathic liver disease, which may harbor rare genetic causes. This study assessed the clinical utility of whole-exome sequencing (WES) and clinical-exome sequencing (CES) in idiopathic liver disease patients and explored candidate variants using in silico approaches.

Methods: WES was performed in 10 unrelated patients with idiopathic liver disease, and CES was performed in two additional patients. Variants were prioritized and classified per American College of Medical Genetics and Genomics (ACMG) guidelines. In cases without a definitive genetic diagnosis, further in silico analyses were conducted using STRING, DAVID databases, alongside multiple pathogenicity prediction tools, to identify potential candidate genes and variants.

Results: A definitive molecular diagnosis was established in four patients, with pathogenic/likely pathogenic variants identified in ABCB4 (c.181_182del), ATP7B (c.3688A > G; c.2138A > G), SLC10A1 (c.568-1G > A), and FOCAD (c.187C > T). In undiagnosed cases, 138 candidate variants were prioritized including high potential disease-associated variants in MYH9, GALK1, SLC25A20, MAN2B2, and MVK genes. Pathway enrichment analysis revealed no shared biological pathway, but taste and olfactory signaling pathways were enriched in two cases.

Conclusion: WES/CES yielded actionable diagnosis in considerable number (33%) of patients and identified novel candidate variants in unresolved cases, supporting its integration into clinical workflows for rare liver disorders.

Keywords: ABCB4; FOCAD; clinical exome sequencing; idiopathic liver disease; whole exome sequencing.