Unexplained Liver Disease Diagnosed by Whole-Exome Sequencing

Chronic liver disease is a significant health problem affecting more than four million people and leading to over 40,000 deaths annually in the United States alone. It often remains undiagnosed for many years until overt manifestations of chronic liver disease emerge and liver injury has already reached catastrophic proportions.

Adult patients suffering from unexplained liver disease represent an understudied and underserved population, and, furthermore, the use of whole-exome sequencing (WES) to diagnose the disease remains poorly studied.

To correct this deficiency, investigators at Yale School of Medicine (New Haven, CT, USA) performed WES and deep phenotyping of 19 unrelated adult patients with idiopathic liver disease following an ambiguous conventional work-up performed by a hepatologist. WES is a technique for sequencing all the approximately 20,000 human protein-coding genes. It is suitable for both clinical use and translational research studies.

The investigators reported that in five cases, genomic analysis led to diagnosis and informed treatment and management of the disease. For example, in one case, molecular diagnosis enabled initiation of leptin replacement therapy that restored liver function and decreased daily insulin requirements. In two of the cases, a mitochondrial disorder due to a homozygous pathogenic variant enabled initiation of disease preventive measures including supplementation with antioxidants.

"This study provides evidence that a subset of adult patients who suffer from liver disease of indeterminate etiology with or without other comorbidities harbor an underlying Mendelian disorder, which may be unrecognized during their entire childhood until genetic testing is performed," said senior author Dr. Silvia Vilarinho, assistant professor of medicine and pathology at Yale School of Medicine. "Our data highlight the importance of using WES in the investigation of liver disease of unknown cause so that we may start developing an understanding of what clinical presentations or diseases are genetic and may remain undiagnosed until adulthood."

"Advances in human genomics through next generation sequencing technology have created an unprecedented opportunity for genetic investigation and clinical diagnosis," said Dr. Vilarinho. "However, to date, most studies that investigate the use of next generation sequencing technologies in diagnosis and personalized medical care have been performed in either pediatric or cancer patients. The clinical utility of these approaches for a broader spectrum of diseases among adults remains poorly studied."

The WES study was described in the April 1, 2019, online edition of the Journal of Hepatology.

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