BACKGROUND AND AIMS: In patients with steatotic liver diseases (SLD), genetic factors may account for severe liver involvement despite mild or absence of triggering factors or a strong family history. Aim of this study was to examine the diagnostic uptake of targeted sequencing (TS), covering both coding and non-coding regions, of a broad panel of 82 liver and lipid metabolism genes in patients with unexplained SLD. METHODS: We enrolled 49 adult patients with SLD and a suspected genetic contribution. Genetic variants were detected through a customised TS panel, whereas the contribution of common genetic variation to the individual susceptibility to SLD was captured by a polygenic risk score (SLD-PRS). RESULTS: A diagnosis of rare Mendelian disorder was established in 11 patients (22%), independently of age or family history. Rare variants possibly contributing to clinical phenotype were detected in additional 29 patients (59%). Increased SLD-PRS values were detected in 17 patients (35%), enabling an increase in diagnostic uptake of 24%, especially in those without a strong family history (p = 0.03). Genetic diagnosis allowed refinement of clinical management in 23 (47%) patients. CONCLUSIONS: The diagnostic uptake of TS was 22% for Mendelian disorder and 59% for possible contribution to clinical phenotype in selected adult patients with SLD. Evaluation of common variants, as captured by SLD-PRS, yields complementary information increasing the overall utility of the genetic examination.