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Reuters Health Information: Whole exome sequencing shows promise in diagnosing unexplained liver disease

Whole exome sequencing shows promise in diagnosing unexplained liver disease

Last Updated: 2019-04-24

By Marilynn Larkin

NEW YORK (Reuters Health) - Whole exome sequencing (WES) may identify genetic causes of idiopathic liver disease after an unrevealing conventional workup, researchers say.

"The impact of WES has been most noticeable in pediatric disorders and oncology, but its utility in the adult liver clinic is recently emerging," Dr. Sylvia Vilarinho of the Yale Liver Center in New Haven told Reuters Health by email.

WES involves sequencing approximately 20,000 human protein-encoding genes.

"This study supports the incorporation of WES in the diagnostic and management algorithms of adults suffering from idiopathic liver disease despite a comprehensive work-up, and underscores its value as a means of developing an understanding of what liver phenotypes of unknown cause in adults are genetic," Dr. Vilarinho said. "The center/physician offering this test should be able to provide adequate genetic counseling and equipped to handle 'incidental' findings."

Dr. Vilarinho and colleagues performed WES and deep phenotyping of 19 unrelated adults with idiopathic liver disease who had undergone a comprehensive workup that did not yield a diagnosis, as reported online April 15 in the Journal of Hepatology. WES yielded an actionable diagnosis in five, all of whom received family counseling.

Four patients had monogenic disorders. One, a 33-year old woman of European descent, had an undiagnosed type 3 familial partial lipodystrophy due to a deleterious heterozygous variant in PPARG and had endured severe complications for 18 years. She was started on leptin replacement therapy, resulting in normalization of liver aminotransferases, amelioration of dyslipidemia, and decreases in daily insulin requirements.

Two patients, a 32-year old woman of African descent and a 28-year-old man of European descent, were diagnosed with MDR3 deficiency due to recessive mutations in ABCB4. One was a transplant candidate and the other, a candidate for retransplantation.

The fourth patient, a lean 32-year old man of European descent, had been diagnosed with non-alcoholic steatohepatitis, He harbored a mitochondrial disorder due to a homozygous pathogenic variant in NDUFB3; preventive measures were initiated, including antioxidant supplementation.

The fifth patient, a 24-year-old Asian man, had hepatic steatosis of unknown etiology. He was found to have a damaging heterozygous variant in APOB and vitamin E supplementation was considered.

"This study supports the use of WES in the evaluation and management of adults with idiopathic liver disease in clinical practice," the authors conclude.

Dr. Vilarinho said, "Reminiscent of the widely accepted Radiology and Pathology Rounds in clinical practice, this study illustrates the potential clinical value of Genome Rounds in the individual assessment and medical care of adults suffering from liver disease of unknown cause. A multidisciplinary Genome Rounds approach will likely create the basis to develop best practice guidelines for genomic medicine in a variety of non-oncological medical and surgical specialties, including hepatology."

Dr. David Finegold, a professor in the Department of human genetics at Pitt Public Health, University of Pittsburgh, commented, "WES is now broadly available in a wide range of genomics laboratories, both hospital-based and commercial. The interpretation of this data is profoundly challenging and absolutely requires special expertise within the laboratory."

"The downsides to WES are several," he told Reuters Health by email. "There is significant expense, although compared to the past, and the care required to maintain undiagnosed patients, this is usually not an impenetrable obstacle. The performance of this test is technically demanding and the interpretation must be done by highly skilled individuals who understand the nuances related to identification of genetic variance."

"Moreover," he said, "there is the risk of identifying variance that has no direct relationship to the patient's liver disease but places them at high risk of other disorders. Dealing with these findings, such as a BRCA1 mutation, is challenging."

Dr. Hardeep Singh, a gastroenterologist at St. Joseph Hospital in Orange, California, told Reuters Health that 20%-30% of patients with cirrhosis are cryptogenic. "This means the workup for all known viral, metabolic and autoimmune causes of cirrhosis was negative," he said by email. "We assume most of these patients have fatty liver disease, but based on this paper, some may have genetic disorders that were not (previously) diagnosed. I'm not sure all of the findings will be actionable, because once cirrhosis is already present, there may not be anything that can be reversed."


J Hepatol 2019.

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