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

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.

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 JAG1 or NOTCH2. Potential diagnoses involved one pathogenic/likely pathogenic variant in autosomal recessive genes plus one variant of uncertain significance.

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 JAG1, SERPINA1, ABCC2, ABCB11, CFTR, POLG, and NOTCH2. Potential diagnoses commonly involved ABCC2, ABCB4, ABCB11, CFTR, and PKHD1. Monoallelic variants were frequent in SERPINA1, CFTR, DHCR7, ABCB4, and PKHD1.

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.