Advancing diagnosis and management of liver disease in adults through exome sequencing

Abstract

Background: 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.

Methods: 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.

Findings: 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.

Interpretation: 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.

Funding: 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.

Keywords: Genetic disorder; Genomics; Idiopathic liver disease; Next generation sequencing; Undiagnosed disease.

Fig. 1

Flow diagram of variant and candidate gene filtering strategy. AR, autosomal recessive; AD, autosomal dominant; OMIM, Online Mendelian Inheritance in Man.

Fig. 2

Proportion of patients in whom a genetic diagnosis was attained versus who remain undiagnosed across the different primary liver phenotype classifications.

Fig. 3

Proportion of patients in whom a genetic diagnosis was attained versus who remain undiagnosed according to age (< or $\ge$40 years-old), presence or unknown/absence of family history and sex.