Clinical utility of a targeted panel sequencing for the diagnosis of chronic hereditary liver diseases in adult patients

• Published in: Digestive and liver disease 2023-03, Vol.55, p.S35-S35
• Main Authors: Marini, I., Ronzoni, L., Pelusi, S., Golfetto, F.S., Lombardi, A., Rondena, J., Periti, G., Bianco, C., Passignani, G., Castronovo, P., D'Ambrosio, R., Finelli, P., Prati, D., Valenti, L.
• Format: Article
• Language: English
• ISSN: 1590-8658; 1878-3562
• DOI: 10.1016/j.dld.2023.01.068

The pathogenesis of chronic liver diseases (CLD) remains often unexplained despite extended clinical and instrumental evaluations. Next-generation sequencing (Whole Exome [WES] or Targeted Panel Sequencing [TS]), may improve the diagnostic rate of rare genetic disorders also in adults, but they are not yet widely clinically available. To evaluate the clinical utility of a TS approach in diagnosis CLD in adult patients. We analyzed 57 unrelated adult patients with CLD of suspected hereditary etiology, using a Haloplex Customized TS including 82 selected liver-diseases causing genes. Sequencing was performed on MiSeq and data were analyzed using SureCall and wANNOVAR softwares. All variants were confirmed by Sanger sequencing. Patients’ phenotypes were divided into four categories: iron overload, dyslipidemia, cholestatic diseases and fatty liver diseases. Overall, TS allowed to reach a definitive genetic diagnosis in 15 patients (diagnostic yield: 26%). Likely pathogenic variants or rare variants of unknown significance, (VUS) but with a high likelihood of altering protein function, were identified in 26 patients, providing a diagnostic rate of 46% for genetic contribution to the phenotype. A total of 16 cases (28%) remained undiagnosed. Stratifying according to the clinical phenotypes, the higher diagnostic yield was obtained in patients with dyslipidemia (36%) and iron overload (30%) (Table 1). TS proved to be a useful first-tier genetic test for the diagnosis of selected adult patients with CLD, mainly if the clinical phenotype is well defined, as in dyslipidemia or iron overload cases. Moreover, TS allowed to identify genetic variants possibly contributing to disease phenotype in a high number of patients, expanding disease pathogenesis understanding. In undiagnosed cases, more extensive analysis, such as WES and determination of genetic predisposition to fatty liver disease progression, as captured by polygenic risk scores, should be performed.