全外显子组测序（WES）是一种有效的诊断工具，可用于那些经过全面临床检查却仍然没有诊断结果的患者。虽然WES在儿科和肿瘤学领域的应用越来越广泛，但在非肿瘤成人医学中的使用仍然不足，包括肝病患者，部分原因是基于错误的观点，即成年人很少携带具有大效应的罕见遗传变异。在这里，我们旨在评估两个重大三级转诊学术医疗中心成年人肝病患者罕见遗传变异的负担。我们在两个美国大型学术医疗中心评估的52名未明确病因的成年肝病患者中进行了WES分析，配合全面临床评估。外显子分析发现33%的患者（17/52）有明确或推测的诊断，为他们的疾病发病机制提供了新的认识，其中大多数患者（12/17）没有已知的家族肝病史。我们的数据显示，在未明确病因的肝病患者中，超过三分之二的具有遗传诊断的病例正在接受胆汁淤积或肝脂肪变性的评估。本研究揭示了成人中遗传疾病发生率和谱的被低估情况，并强调在评估和管理未明确病因的成人肝病患者中结合外显子组测序的临床价值。S.V.受到NIH/NIDDK（K08 DK113109和R01 DK131033-01A1）和Doris Duke慈善基金会资助（授予编号：2019081）。该工作部分得到了NIH资助的耶鲁肝脏中心（P30 DK34989）的支持。版权所有©2023作者。由Elsevier B.V.出版。保留所有权利。

Whole-exome sequencing (WES) is an effective tool for diagnosis in patients who remain undiagnosed despite a comprehensive clinical work-up. While WES is being used increasingly in pediatrics and oncology, it remains underutilized in non-oncological adult medicine, including in patients with liver disease, in part based on the faulty premise that adults are unlikely to harbor rare genetic variants with large effect size. Here, we aim to assess the burden of rare genetic variants underlying liver disease in adults at two major tertiary referral academic medical centers.WES analysis paired with comprehensive clinical evaluation was performed in fifty-two adult patients with liver disease of unknown etiology evaluated at two US tertiary academic health care centers.Exome analysis uncovered a definitive or presumed diagnosis in 33% of patients (17/52) providing insight into their disease pathogenesis, with most of these patients (12/17) not having a known family history of liver disease. Our data shows that over two-thirds of undiagnosed liver disease patients attaining a genetic diagnosis were being evaluated for cholestasis or hepatic steatosis of unknown etiology.This study reveals an underappreciated incidence and spectrum of genetic diseases presenting in adulthood and underscores the clinical value of incorporating exome sequencing in the evaluation and management of adults with liver disease of unknown etiology.S.V. is supported by the NIH/NIDDK (K08 DK113109 and R01 DK131033-01A1) and the Doris Duke Charitable Foundation Grant #2019081. This work was supported in part by NIH-funded Yale Liver Center, P30 DK34989.Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.