Clinical utility of an evolving cholestasis gene panel in 10,000 children and adults.

Objective: Cholestasis has diverse causes, with genetic factors playing a key role. Diagnosis is challenging due to varied presentations and overlapping genetic conditions. Next-generation sequencing cholestasis gene panels enable faster, more accurate identification of genetic causes. This study summarizes results from more than 10,000 tests, highlighting their clinical utility. Methods: We analyzed aggregate data from a 77-gene cholestasis panel used between 2016 and 2022. Eligible patients had unexplained cholestasis or chronic liver disease. DNA sequencing utilized custom capture libraries (SureSelect 2016-2021 and PGxome® 2021-2022). Variants were classified per ACMG/AMP guidelines. Definitive diagnoses required biallelic pathogenic/likely pathogenic variants in autosomal recessive genes or a single pathogenic/likely pathogenic variant in autosomal dominant Results: Of 10,894 samples analyzed, 51.1% were from patients less than 1 year old and 9.2% from those 18 years of age or older. Overall, 2917 patients carried one or more pathogenic or likely pathogenic variant(s). Diagnostic yield was 6.8% for definitive and 2.2% for potential diagnoses. Definitive findings were most common in Conclusions: These cholestasis gene panel results reinforce their value in diagnosing and identifying complex genetic causes of cholestasis, especially in infants less than 1 year old. Early detection supports timely intervention, and the panel provides clearer insight to support accurate diagnoses and inform potential therapeutic strategies.