Novel panel identifies variants in unexplained cholestatic cases

The researchers say that their phenotype-driven approach facilitates the discovery of novel genes related to the condition, and the aim is to make the panel available to adult and pediatric patients, once their findings have been validated.

Previous research has indicated that approximately 30% of patients with isolated/primary cholestasis lack mutations in genes that are known to be associated with the condition, resulting in an unmet need in patient care, say the researchers.

“We get all these very difficult cases that have had genetic testing, either with a small gene panel, or, in one patient, whole genome sequencing,” but a causative alteration has not been identified, presenter Chunyue Yin (Center for Undiagnosed and Rare Liver Disease (CURL), Cincinnati Children’s Hospital, Ohio, USA) told medwireNews.

Consequently, the team developed the CURL Panel, which utilizes exome sequencing technology and phenotype-driven analysis to focus on a predefined list of 1445 genes related to the liver. This can include “just genes expressed in the liver; we do not know if they are associated with any disease,” said Yin.

She noted that gene knockout can then be done very quickly at her institution in order to determine if a gene is linked to a phenotype and therefore relevant.

The study included patients with a referral for unexplained adult or pediatric chronic cholestasis or recurrent liver failure, in which a genetic diagnosis is likely to be of benefit.

Since June 2024, over 50 patients have been screened, with sequencing completed in 14; a whole-exome method was used in eight patients, after which a whole-genome method was adopted for the study.

Clinical phenotypes and variants were identified in six patients, with three novel variants in the ATP6AP1, PLEC, and LARS genes, and three variants in the ABCB4, ABCB11, and NOTCH2 genes that have previously been linked to cholestasis.

Yin said that they plan on completing sequencing in a further 20 patients over the next 2 years. “If it goes well, we are going to expand this,” she added, making it available to patients outside our clinic.

The team also plans to continue updating the panel to include further genes as they become known. “We are still developing this,” Yin underlined, and novel genes and variants of unknown significance will be further investigated using cell culture and animal studies to validate their role in cholestasis.