Targeted gene sequencing panel resolves unexplained cholestasis in about 5% of adults

The panel also identified a potential genetic contribution in 41.6% of the 310 adults with unexplained cholestatic phenotypes who had no alternative or prior genetic diagnoses.

“These findings highlight the value of genetic testing in the diagnostic work-up of adult patients with unexplained cholestatic liver disease,” say Daphne D’Amato (University of Milano-Bicocca, Monza, Italy) and colleagues.

They add: “NGS panel results help to tailor follow-up and counselling for patients (and their relatives) with definitive diagnosis and may offer contributory insights for 41.6% of patients.”

The team notes that “systematic re-evaluation and data-sharing may upgrade contributory findings to definitive diagnoses over time.”

The observational study involved adults from nine Italian tertiary centers with cholestatic phenotypes, who had diagnostic work-up involving clinical, biochemical, imaging, and histologic assessments.

In all, 72.9% of patients had chronic unexplained cholestasis, defined as alkaline phosphatase and gamma-glutamyl transferase levels above the upper limit of normal for at least 6 months and no known secondary causes such as primary biliary cholangitis or primary sclerosing cholangitis. The other phenotypes included intermittent cholestasis in 9.6% of patients, low-phospholipid associated cholestasis in 8.9%, drug-induced cholestasis in 4.5%, and intrahepatic cholestasis of pregnancy in 2.9%.

DNA sequencing was carried out using the NGS panel, which consisted of 77 “well-established disease-associated genes,” say the investigators.

In all, 98 gene variants were found in progressive familial intrahepatic cholestasis (PFIC) genes, while 430 were found in non-PFIC genes, 131 in genes related to ciliopathies, 117 to inborn errors of metabolism genes, and 112 in genes associated with hepatocellular disease.

The PFIC-related gene variants occurred in a total of 84 patients and were significantly associated with low-phospholipid associated cholestasis (17.9%), drug-induced cholestasis (6.0%), and ICP (4.8%) phenotypes. These PFIC gene variants were also significantly more likely than other variants to be linked to magnetic resonance cholangiopancreatography abnormalities, hepatobiliary complications, cholecystectomy before the age of 40 years, and jaundice, whereas they were significantly less likely to be associated with cirrhosis.

Genetic variants that were classified according to the American College of Medical Genetics and Genomics classification as pathogenic or likely pathogenic variants consistent with the clinical phenotype and inheritance pattern indicated a genetic diagnosis in 17 of the 310 participants.

All but six of these patients had pathogenic or likely pathogenic variants in PFIC-related genes.

In addition, 152 genetic variants that were classified as a hot/warm variant of uncertain significance in disease-related genes were considered to make a possible phenotypic contribution in 129 patients, with 108 patients having one variant, 19 having two variants, and two patients having three variants.