Exome Sequencing in Adults with Unexplained Liver Disease: Diagnostic Yield and Clinical Impact

Background: The etiology of liver disease remains unidentified in approximately 30% of patients, presenting a persistent diagnostic challenge. While whole-exome sequencing (WES) is well established for identifying rare genetic conditions in pediatric populations, its utility in adult hepatology is less defined. This study aimed to evaluate the diagnostic value of WES in adults with unexplained liver disorder. Methods: Fifty-three Turkish adult patients with idiopathic liver disease underwent a comprehensive clinical evaluation and WES at Gazi University Ankara in 2024-2025. The cohort included individuals with idiopathic cholestasis (6/53, 11%), hepatic steatosis (28/53, 53%), unexplained elevated liver enzymes (12/53, 23%), and cryptogenic cirrhosis (7/53, 13%). All patients had inconclusive results from prior standard investigations. Results: ES yielded a definitive molecular diagnosis in 11% (6/53) of cases. Definitive diagnoses were distributed across the following disease categories: idiopathic cholestasis (n = 1), hepatic steatosis (n = 1), elevated liver enzymes (n = 2), and cryptogenic cirrhosis (n = 2). Pathogenic variants were detected in the ABCB4, AGL, APOB, CP, and MTTP genes. One patient was identified with mosaic Turner syndrome. Conclusions: This study highlights the role of rare genetic variants in the etiology of unexplained liver disease in adults. Integrating whole-exome sequencing into hepatology practice can uncover novel disease mechanisms and improve diagnostic yield, informing more precise patient care.