Author: Lynda Williams
medwireNews: Whole-exome sequencing (WES) led to definitive diagnoses for almost a quarter of patients with unexplained adult-onset cholestatic liver disease, say Italian researchers.

Miki Scaravaglio (University of Milano-Bicocca) and co-workers explained at the 2024 AASLD The Liver Meeting in San Diego, California, USA, that “genetic testing in adults with unexplained cholestasis has mostly focused on progressive familial intrahepatic cholestasis (PFIC) genes.”
To investigate further, the researchers used WES to assess a wider panel of 494 genes associated with cholestasis and liver disease.
The 21 participants (47.6% men) were aged an average of 33.3 years at time of disease onset and an average 42.8 years at the time of their genetic test.
Overall, the WES detected 575,186 variants, of which 277 pathogenic or rare functional variants were detected in 155 of the liver-related genes. This included 14 variants present in six different genes previously linked to PFIC, 68 variants among 37 non-PFIC genes linked to cholestasis, and 195 variants among 113 genes linked to other liver diseases.
Clinical phenotype was strongly associated with the likelihood of genetic diagnosis, with a diagnosis confirmed for both of the two patients with recurrent lithiasis, 14.3% of the seven patients with intrahepatic cholestasis, and 16.7% of the 12 patients with primary sclerosing cholangitis (PSC) with unusual features. For the latter two groups, 85.7% and 66.6%, respectively, had variants in genes that might be linked to their phenotype.
Thus, overall, 23.8% of study participants received a definite genetic diagnosis, 66.7% had one or more variants that might be linked to their clinical phenotype, and just 9.5% had no genetic indicators identified at all, Scaravaglio et al summarise.
Cholestasis liver disease in a first-degree relative was found in half of patients with recurrent lithiasis, 28.6% of those with intrahepatic cholestasis, and 33.3% of those with PSC. The corresponding rates of pruritus were 0%, 28.6% and 8.3%.
The researchers conclude: “Pending confirmatory results from large-scale and functional validation studies, this proof-of-principle study demonstrates that the integration of WES in the diagnostic workflow of cholestatic liver diseases in adults may increase the diagnostic yield of rare cases of inherited cholestatic and liver disorders and highlight novel pathogenic mechanisms.”
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AASLD The Liver Meeting; San Diego, California, USA: 15–19 November 2024