Genetic sequencing uncovers causes for mysterious liver disease in adults

In up to 30% of individuals with chronic liver disease, the cause is unknown. To test for possible genetic factors in such cases, Yale researchers conducted whole-exome sequencing for a small group of patients, finding specific mutations that would have otherwise been missed. The results led to accurate diagnoses and informed treatment for a subset of the patient participants, the researchers said.

Genetic sequencing for individuals with liver disease has been most often done in children. This Yale-led study leads the way to explore the genetics of unexplained liver disease in adults, said senior author Silvia Vilarinho, assistant professor of medicine and of pathology. After excluding patients with excessive alcohol use, and performing comprehensive clinical exams, the research team recruited 19 individuals for the study.

With whole exome sequencing — which probes the roughly 20,000 protein-coding genes in an individual’s genome — the researchers identified four genetic disorders in five patients. In one particular case, a single mutation in the PPARG gene was determined to be the cause of disease for a patient who had suffered severe complications for nearly two decades. With this accurate diagnosis, the patient is being treated with leptin replacement therapy, which has allowed her to reduce her insulin intake and see improved liver function tests.

Vilarinho and her colleagues will continue to recruit patients and seek answers for the remaining undiagnosed cases, whose liver disease might be caused by some as yet undiscovered gene variants. “In our study we saw we had an impact in the lives of five people by providing a diagnosis,” she noted. As the cost of sequencing decreases, the researchers recommend greater use of genomic analysis. “It should be incorporated in the algorithm of evaluating patients with liver disease of unknown cause,” said Vilarinho.

The study is published in the Journal of Hepatology.

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