As genetic testing becomes more integrated into hepatology, clinicians are increasingly faced with challenges regarding how to interpret results and incorporate them into a broader diagnostic framework. In this segment of Liver Lineup: Updates & Unfiltered Insights, guests Robert Gish, MD, and Saul Karpen, MD, PhD, explore the complexities of genetic interpretation, the evolving role of multidisciplinary evaluation, and how traditional tools like biopsy remain essential in the era of genomics.
Check out the full episode here.
Gish highlighted the limitations of relying solely on genetics, noting that referrals to major academic centers for additional interpretation often yield limited new insights unless more expansive approaches, such as whole-exome or whole-genome sequencing, are pursued. Instead, he has shifted toward a more selective and clinically driven use of genetic consultation, reserving referrals for targeted scenarios such as rare diagnoses, complex counseling questions, or reproductive planning.
At the same time, genetic testing can uncover unexpected and actionable findings. Gish described a patient with atypical cholestatic liver disease who was ultimately diagnosed with lysosomal acid lipase deficiency, a rare condition that would have been difficult to identify without genetic evaluation. In another case, identification of dual heterozygous variants helped explain overlapping pulmonary and hepatic disease, reinforcing the concept that multiple genetic factors can interact to shape clinical presentation.
This concept, referred to as “synergistic heterozygosity,” is gaining increasing recognition in hepatology. Rather than a single causative mutation, patients may harbor multiple variants that collectively contribute to disease. This paradigm challenges traditional binary thinking and underscores the importance of interpreting genetic results in clinical context.
A major continued barrier to adoption, however, is the interpretation of variants of uncertain significance (VUS). Gish argued that this terminology can be misleading and counterproductive, preferring instead a more pragmatic approach that emphasizes clinical correlation. For hepatologists, this means integrating genetic findings with other core elements of liver disease evaluation, including laboratory testing, imaging, and histology.
Indeed, both Gish and Karpen emphasized that genetic testing should complement established diagnostic tools rather than replace them. Liver biopsy, in particular, continues to play a critical role, especially when genetic findings are inconclusive. Histologic evidence of cholangiopathy or other structural abnormalities can help validate the clinical relevance of a genetic variant and, in some cases, contribute to its reclassification as pathogenic.
Karpen also highlighted the dynamic nature of genetic interpretation. A result considered inconclusive today may be better understood in the future as additional data emerge. In some cases, reanalysis of prior genetic testing has led to new diagnoses, reflecting the rapidly evolving knowledge base in genomics.
Editors’ note: Relevant disclosures for Reau include AbbVie, Gilead, Salix, Arbutus, and VIR. Relevant disclosures for Brown include Mallinckrodt Pharmaceuticals, Gilead, Salix, Intercept, Ipsen, and Madrigal. Relevant disclosures for Karpen include Mirum and Ipsen. Relevant disclosures for Gish include Abbott, AbbVie, Aligos, Altimmune, Arrowhead, AstraZeneca, Corcept, Genentech, Gilead Sciences, GSK, Intercept, Janssen, Merck, Perspectum, Pfizer, and others.
