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Unexplained Liver Disease Cases Diagnosed by Exome Sequencing

NEW YORK (GenomeWeb) – New research suggests that exome sequencing can unearth diagnostically relevant mutations in a subset of adults with unexplained liver disease.

In a study published today in the Journal of Hepatology, researchers from Yale University School of Medicine and the University of Michigan presented results from a deep-phenotyping and exome sequencing-based analyses of 19 unrelated individuals with forms of liver disease that could not be explained by known mutations or conditions. In five of those idiopathic liver disease cases, the exome sequencing data led them to diagnoses by uncovering four monogenic conditions.

"[W]e provide data to support the utility of WES in the diagnosis and management of adults with liver disease of unknown cause with or without involvement of other diseases and/or unusual clinical findings," co-senior and corresponding author Silvia Vilarinho, a researcher in the departments of internal medicine and pathology at Yale, and her colleagues wrote.

Using Illumina instruments, the researchers sequenced protein-coding portions of the genome in 19 individuals with unexplained liver disease and no history of excessive alcohol use who were recruited at Yale between October 2015 and August 2018. The patients were diagnosed with liver problems between the ages of 22 and 73 years, they noted, and included some individuals with co-morbid conditions.

Aside from identifying variants through comparisons with the human reference genome, the team relied on a read depth normalized proprietary program to pick up potential copy number variants in the exomes. Together, these data led to diagnoses for five 24- to 33-year-old patients of Asian, European, or African ancestry, who were affected by four distinct single-gene conditions.

Tracking down the alterations not only helped to diagnose that subset of cases, the researchers explained, but also offered new insights into liver disease biology, the clinical presentations that can be associated with various mutations, and potential treatment avenues for affected individuals.

In one liver disease patient, for example, the team identified a heterozygous mutation affecting the PPARG gene — an alteration associated with a condition called type 3 familial partial lipodystrophy — that led the researchers to a leptin replacement therapy that improved several of that individual's symptoms.

The researchers also unearthed recessive mutations in the ABCB4 gene, which encodes multidrug resistance protein 3, in two affected individuals, producing a deficiency of the protein. And in the last two patients, the exome data pointed to homozygous NDUFB3 and heterozygous APOB gene variants contributing to non-alcoholic steatohepatitis and hepatic steatosis, respectively.

Based on these findings, the authors suggest that "a subset of adult patients who suffer from liver disease of indeterminate etiology with or without other co-morbidities harbor an underlying Mendelian disorder, which may be unrecognized during their entire childhood until genetic testing is performed."

In a related editorial in the Journal of Hepatology, a pair of investigators from the Mayo Clinic said the study "highlights the importance of WES testing for diagnosing Mendelian diseases among adult patients with unexplained liver diseases even in the absence of family history."

Filippo Pinto e Vairo and Konstantinos Lazaridis, the authors of that editorial, noted that the newly-diagnosed individuals were all younger than 40 years, suggesting that the exome sequencing approach may be particularly beneficial for younger patients. 

Indeed, based on findings from the new study and from research published previously, "we advocate the use of WES testing in the clinic for adult patients with idiopathic liver disease," they wrote, but "reserve this suggestion" for patients showing signs or symptoms of disease prior to their 40th birthday.