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Exome Sequencing Reanalysis Improves Molecular Diagnosis in Genetic Cholestatic Liver Diseases
Maël Silva Rodriguez1, Adel Larbaoui2, Mélissa Largo2
1Department of Genomic Medicine, Division of Biochemistry, Molecular Biology, and Nutrition, University Hospital of Nancy, F-54000 Nancy, France; Reference Center for Inborn Errors of Metabolism (ORPHA67872), University Hospital of Nancy, F-54000 Nancy, France; Faculty of Medicine of Nancy, University of Lorraine, F-54000 Nancy, France; INSERM UMR_S 1256, Nutrition, Genetics, and Environmental Risk Exposure (NGERE), F-54000 Nancy, France.
Background And Aims:
The 2024 European Association for the Study of the Liver (EASL) guidelines recommend periodic reanalysis of exome data in genetic cholestatic liver diseases, although supporting evidence remains limited and optimal gene panel composition has not been established. We evaluated the molecular diagnostic yield of systematic reanalysis of clinical exome sequencing (CES) data and compared cholestasis-focused gene panels.
Methods:
Consecutive patients referred for CES at a tertiary center for suspected genetic cholestatic liver disease (January 2021 to February 2025) were included. The initial analysis (A1) was compared with a reanalysis (A2) using three in silico panels: the Cholestasis Nancy Panel (41 genes), the EASL 2024 panel (18 genes), and an LPAC panel (8 genes). The primary endpoint was the difference in likely pathogenic or pathogenic (LP/P) yield between A1 and A2. The secondary endpoint added variants of uncertain significance (VUS).
Results:
Among 86 patients (median age 35 years; 63% female; 83% adults), the LP/P yield increased from 30% (26/86) to 43% (37/86) (95% CI, 5-21; P=0.006). At reanalysis, the Cholestasis Nancy Panel provided an incremental diagnostic yield beyond the Cholestasis EASL 2024 core panel at both thresholds (43% vs 34%, P = 0.013; 69% vs 49%, P=0.0001). At the LP/P threshold, the incremental yield was significant for cholelithiasis/LPAC (P=0.004) but unchanged for unexplained cholestasis, Alagille syndrome, and BRIC/PFIC. At the VUS/LP/P threshold, the increase was also significant for unexplained cholestasis (P=0.003). SERPINA1 was the most frequently implicated gene.
Conclusions:
Systematic CES reanalysis increases molecular diagnostic yield in genetic cholestatic liver diseases, particularly in clinically challenging presentations. Performed within an accredited CES platform, periodic reappraisal of data as knowledge evolves warrants integration into routine practice.
Clinical Trial Number:
Not applicable.
