Clinical utility of genomic analysis in adults with idiopathic liver disease

Abstract

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 study of a broader spectrum of non-oncological diseases, among adults, remains poorly studied. We assessed the utility of WES in 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 nineteen unrelated adult patients with idiopathic liver disease recruited at a tertiary academic health care center. Results: Analysis of the exome in 19 cases identified four monogenic disorders in five 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

Exome Sequencing in Clinical Hepatology

“…However, the absence of positive family history should not deter any physician from pursuing genomic analysis if any of the other features are present. In fact, in our series, none of the 5 adult patients with idiopathic liver disease who attained a genetic diagnosis reported a family history of liver disease. Lastly, as WES is getting more widely used in clinical practice, it is already replacing the conventional single‐gene and gene‐panel tests in large academic centers.…”

“…As an example, hemochromatosis could be due to loss‐of‐function mutations in five distinct genes, namely HFE , HJV , HAMP , TFR2 and SLC40A1, but only HFE gene is typically sequenced. In a recent study of 19 patients with idiopathic liver disease, despite a comprehensive work‐up performed by a hepatologist, WES provided a genetic diagnosis in 5 of these patients (about 25%), uncovering four distinct monogenic disorders . This study identified 5 patients with up to 2 decades of misdiagnosis who in fact harbored Mendelian disorders previously unrecognized and highlight the utility of WES in patients with undiagnosed liver disease.…”

“…Furthermore, we and others have successfully combined WES with deep phenotyping (i.e., detailed characterization of each patient's phenotypic features) to identify the underlying genetic defects in infants and children with idiopathic liver diseases, including children with liver failure of indeterminate etiology . Astute clinical annotation (i.e., comprehensive phenotype description of the patient) is central to harnessing the maximal potential of genomic data . Notably, the vast majority of these studies have been performed in pediatric populations and in cancer patients.…”

“…Notably, the vast majority of these studies have been performed in pediatric populations and in cancer patients. Hence, the value of WES in the diagnosis and management of adult patients with nononcological diseases is only recently emerging . In fact, in adult hepatology clinic, Wilson's disease, hemochromatosis, and alpha‐1 antitrypsin deficiency are routinely investigated as part of a comprehensive work‐up for liver test abnormalities and/or advanced liver disease by using single gene and/or gene panel test(s).…”

“…Lastly, as WES is getting more widely used in clinical practice, it is already replacing the conventional single‐gene and gene‐panel tests in large academic centers. WES creates the possibility of screening most relevant liver disease genes at once, providing genetic diagnoses across diverse medical subspecialties (Table ), as liver disease can be a presentation of a liver‐focused disorder or the main clinical manifestation of a systemic, multi‐organ, disease as illustrated in Hakim et al Moreover, there are cases in which WES identified mutations in genes known to cause a disease distinct from the initial clinical diagnosis . For example, a pathogenic homozygous mutation in MPV17 that causes a hepatocerebral mitochondrial depletion syndrome was identified in a patient with a misdiagnosis of Wilson's disease based on scoring systems described in American Association for the Study of Liver Diseases and European Association for the Study of the Liver guidelines .…”