Next generation sequencing may offer diagnoses in adult unexplained cholestasis

The results, presented at AASLD The Liver Meeting in Washington, DC, USA, support the clinical utility of gene panel-based sequencing, the team says.

Study author Wikrom Karnsakul (Johns Hopkins University School of Medicine, Baltimore, Maryland, USA) told medWireNews that 70% of individuals in their overall cohort are children, and that the use of a gene panel for cholestasis in adult patients is “relatively new.”

He continued: “We like to bring knowledge from pediatric practice into the adult world” to help people with an unexplained condition that may have been present since childhood to receive a definitive diagnosis.

Karnsakul added that another aim of sharing their experiences in adults in this way is to help hepatologists feel comfortable ordering a gene panel, as they may have “been practicing medicine for a long time but the last time they heard about a gene panel was in medical school.”

Tiziano Pramparo (Mirum Pharmaceuticals, Inc., Foster City, California) added that they are expanding the content of the gene panel so that physicians can reach a diagnosis more quickly and get patients “better treatment more promptly.” The test, he said, may be at a “very early stage” but it is “really highly informative” and helpful for patient care.

The researchers included adult patients with a current or previous history of cholestasis without an identifiable cause, or unexplained chronic liver disease. Between March 2016 and January 2022, they used a custom-designed 77-gene cholestasis panel with optimized capture libraries to perform DNA sequencing, with the aggregate data then reviewed and any variants classified.

The variants were divided into those that were pathogenic or likely pathogenic in line with the known inheritance of the disorder, indicating a definitive diagnosis; variants of unknown significance (VUS), pointing to a potential diagnosis when genes with one pathogenic or likely pathogenic allele were paired with a VUS; and benign or likely benign monoallelic variants.

The study included 856 patients aged 18–88 years, in whom 261 pathogenic and 40 likely pathogenic variants were identified across all genes, alongside 1255 variants of uncertain significance.

The researchers were able to provide a definitive diagnosis in 4.0% of patients who had variants in genes such as ABCB11, ABCC2, CFTR, POLG, and SERPINA1, and a potential diagnosis in 3.5%, which included variants in the ABCB11, ABCB4, ABCC2, CFTR, and PKHD1 genes. Together, this gave an overall diagnostic yield of 7.5%.

In addition, heterozygous variants of uncertain significance were identified in the DHCR7, JAG1, NOTCH2, PEX1, and TJP2 genes, while homozygous variants of uncertain significance were found in the ABCB4, ATP8B1, and JAG1 genes.

The researchers hope to combine genetic, clinical, and functional data from pooled analyses and further studies to further improve diagnostic accuracy by reclassifying these variants of uncertain significance.