Role of rare and common variants in the diagnosis of adults with cryptogenic liver and lipid disorders

Background Chronic liver diseases (CLD) remain undiagnosed in up to 30% of adult patients despite extensive clinical and instrumental workup. Genetic analysis may help in providing a diagnosis, but they are not yet widely clinically available. Aim To evaluate the clinical utility of genetic analysis in diagnosis CLD in adult patients. Materials and Methods A total of 70 unrelated adult patients with liver and lipid disorders with suspected genetic contribution were evaluated; four clinical subgroups were considered: cholestasis, hyperferritinemia, dyslipidemia, and steatotic liver disease (SLD). For each patient we detected the presence of rare variants, through a Next-generation Sequencing Customized Targeted Panel (TS), including 82 liver and lipid metabolism-related genes, and evaluated the contribution of common risk variants, as captured by poligenic risk score (PRS), to the individual susceptibility to SLD. Results A total of 82 clinically relevant rare variants was detected in 54 patients, allowing to establish a clinical diagnosis of a Mendelian disorder in 20 patients (29%). Younger patients were more likely to be diagnosed (OR 0.97; 95% CI: 0.94-1; p= 0.09). Increased SLD-PRS values were detected in 18 patients (26%), 15 of whom (83%) had a SLD phenotype. A positive impact of age and a negative one of family history on high SLD-PRS was detected (p=0.02 and p=0.015, respectively), as well as of clinical phenotype, with SLD being associated with an increased risk (OR 3.58; 95% CI: 1.15-11.18; p=0.003). The presence of a high SLD-PRS could increase the diagnostic uptake of a significant fraction in SLD subgroup and in the overall cohort (+29%, p 0.001 and +15%, p 0.0001, respectively) (Fig.1). Discussion TS is a useful genetic test for the diagnosis of selected adult patients with CLD. The complementary evaluation of common variants, as capture by PRS, may significantly increase the diagnostic uptake for patients with SLD.