Precision Medicine - Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy.
Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
Liver Int. 2022 Apr;42(4):864-870. doi: 10.1111/liv.15185. Epub 2022 Feb 15.
Liver diseases remain unexplained in up to 30% of adult patients; genetic analysis could help establish the correct diagnosis. In six adult patients with cryptogenic liver disease, we performed whole-exome sequencing (WES) and evaluated the individual predisposition to progressive fatty liver disease by polygenic risk scores (PRS). In one patient, WES was allowed to diagnose the Hermansky-Pudlak syndrome. In the other two patients, genetic variants in LDLRAP1/MSH6 and ALDOB genes were identified, contributing to explaining the clinical presentation and disease pathogenesis (50% diagnostic uptake). In the other three patients, rare variants with a high likelihood of disrupting protein function in APOB, ATP7B, ABCB4 and ATP8B1 were identified. One patient who developed hepatocellular carcinoma during the follow-up had a high PRS value. The study supports the role of WES, combined with risk stratification by PRS and accurate clinical assessment in improving the diagnosis and informed management in patients with cryptogenic liver disease, a positive family history or severe fatty liver not fully accounted for by environmental triggers.
在多达 30%的成年患者中，肝脏疾病仍然无法解释；基因分析可能有助于确立正确的诊断。在六名患有不明原因肝脏疾病的成年患者中，我们进行了全外显子组测序（WES），并通过多基因风险评分（PRS）评估了个体进展性脂肪性肝病的易感性。在一名患者中，WES 允许诊断 Hermansky-Pudlak 综合征。在另外两名患者中，发现 LDLRAP1/MSH6 和 ALDOB 基因中的遗传变异，有助于解释临床表现和疾病发病机制（50%的诊断率）。在另外三名患者中，鉴定出 APOB、ATP7B、ABCB4 和 ATP8B1 中具有高概率破坏蛋白功能的罕见变异。一名在随访期间发生肝细胞癌的患者具有较高的 PRS 值。该研究支持 WES 与 PRS 风险分层和准确的临床评估相结合，以改善不明原因肝脏疾病、阳性家族史或环境诱因不能充分解释的严重脂肪性肝病患者的诊断和知情管理。
