Clinical utility of genomic analysis in adults with idiopathic liver disease.

Authors:
Aaron Hakim
Aaron Hakim
Yale University
United States
Xuchen Zhang
Xuchen Zhang
Yale University School of Medicine
New Haven | United States
Angela DeLisle
Angela DeLisle
Yale School of Medicine
Elif A Oral
Elif A Oral
University of Michigan
United States
Daniel Dykas
Daniel Dykas
Yale University School of Medicine
Kaela Drzewiecki
Kaela Drzewiecki
Yale School of Medicine
David N Assis
David N Assis
Yale University School of Medicine
United States
Marina Silveira
Marina Silveira
Institute of Biomedical Sciences
United Kingdom

J Hepatol 2019 Jun 15;70(6):1214-1221. Epub 2019 Apr 15.

Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA; Department of Pathology, Yale School of Medicine, New Haven, CT, USA. Electronic address:

Background & Aims: Adult patients suffering from liver disease of unknown cause represent an understudied and underserved population. The use of whole-exome sequencing (WES) for the assessment of a broader spectrum of non-oncological diseases, among adults, remains poorly studied. We assessed the utility of WES in the diagnosis and management of adults with unexplained liver disease despite comprehensive evaluation by a hepatologist and with no history of alcohol overuse.

Methods: We performed WES and deep phenotyping of 19 unrelated adult patients with idiopathic liver disease recruited at a tertiary academic health care center in the US.

Results: Analysis of the exome in 19 cases identified 4 monogenic disorders in 5 unrelated adults. Patient 1 suffered for 18 years from devastating complications of undiagnosed type 3 familial partial lipodystrophy due to a deleterious heterozygous variant in PPARG. Molecular diagnosis enabled initiation of leptin replacement therapy with subsequent normalization of liver aminotransferases, amelioration of dyslipidemia, and decreases in daily insulin requirements. Patients 2 and 3 were diagnosed with MDR3 deficiency due to recessive mutations in ABCB4. Patient 4 with a prior diagnosis of non-alcoholic steatohepatitis was found to harbor a mitochondrial disorder due to a homozygous pathogenic variant in NDUFB3; this finding enabled initiation of disease preventive measures including supplementation with antioxidants. Patient 5 is a lean patient with hepatic steatosis of unknown etiology who was found to have a damaging heterozygous variant in APOB.

Conclusions: Genomic analysis yielded an actionable diagnosis in a substantial number (∼25%) of selected adult patients with chronic liver disease of unknown etiology. This study supports the use of WES in the evaluation and management of adults with idiopathic liver disease in clinical practice.

Lay Summary: We performed whole-exome sequencing in 19 adult patients with unexplained liver disease after an unrevealing conventional work-up performed by a hepatologist. In 5 cases, genomic analysis led to a diagnosis and informed treatment and management of the disease. Therefore, we suggest using whole-exome sequencing in the evaluation and management of adults with unexplained liver disease.

Download full-text PDF

Source
https://linkinghub.elsevier.com/retrieve/pii/S01688278193011
Publisher Site
http://dx.doi.org/10.1016/j.jhep.2019.01.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6526061PMC
June 2019
5 Reads

Publication Analysis

Top Keywords

liver disease
32
adult patients
16
unexplained liver
12
whole-exome sequencing
12
idiopathic liver
12
management adults
12
genomic analysis
12
disease
10
liver
9
enabled initiation
8
evaluation management
8
unknown etiology
8
adults unexplained
8
heterozygous variant
8
adults idiopathic
8
disease unknown
8
adults
6
patients
5
diagnosis
5
patients chronic
4

Similar Publications