Advancing diagnosis and management of liver disease in adults through exome sequencing.

Autor:	Zheng M; Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA., Hakim A; Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Boston, MA, USA; Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA., Konkwo C; Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA., Deaton AM; Alnylam Pharmaceuticals, Boston, MA, USA., Ward LD; Alnylam Pharmaceuticals, Boston, MA, USA., Silveira MG; Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA., Assis DN; Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA., Liapakis A; Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA., Jaffe A; Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA., Jiang ZG; Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Boston, MA, USA., Curry MP; Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Boston, MA, USA., Lai M; Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Boston, MA, USA., Cho MH; Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA., Dykas D; Department of Genetics, Yale School of Medicine, New Haven, CT, USA., Bale A; Department of Genetics, Yale School of Medicine, New Haven, CT, USA., Mistry PK; Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA., Vilarinho S; Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA; Department of Pathology, Yale School of Medicine, New Haven, CT, USA. Electronic address: silvia.vilarinho@yale.edu.
Jazyk:	angličtina
Zdroj:	EBioMedicine [EBioMedicine] 2023 Sep; Vol. 95, pp. 104747. Date of Electronic Publication: 2023 Aug 09.
DOI:	10.1016/j.ebiom.2023.104747
Abstrakt:	Background: Whole-exome sequencing (WES) is an effective tool for diagnosis in patients who remain undiagnosed despite a comprehensive clinical work-up. While WES is being used increasingly in pediatrics and oncology, it remains underutilized in non-oncological adult medicine, including in patients with liver disease, in part based on the faulty premise that adults are unlikely to harbor rare genetic variants with large effect size. Here, we aim to assess the burden of rare genetic variants underlying liver disease in adults at two major tertiary referral academic medical centers. Methods: WES analysis paired with comprehensive clinical evaluation was performed in fifty-two adult patients with liver disease of unknown etiology evaluated at two US tertiary academic health care centers. Findings: Exome analysis uncovered a definitive or presumed diagnosis in 33% of patients (17/52) providing insight into their disease pathogenesis, with most of these patients (12/17) not having a known family history of liver disease. Our data shows that over two-thirds of undiagnosed liver disease patients attaining a genetic diagnosis were being evaluated for cholestasis or hepatic steatosis of unknown etiology. Interpretation: This study reveals an underappreciated incidence and spectrum of genetic diseases presenting in adulthood and underscores the clinical value of incorporating exome sequencing in the evaluation and management of adults with liver disease of unknown etiology. Funding: S.V. is supported by the NIH/NIDDK (K08 DK113109 and R01 DK131033-01A1) and the Doris Duke Charitable Foundation Grant #2019081. This work was supported in part by NIH-funded Yale Liver Center, P30 DK34989. Competing Interests: Declaration of interests A.M.D., R.A.H., A.M.H., L.K., P.L., P.N., M.E.P., and L.D.W., are employees of Alnylam Pharmaceuticals. A.M.D. and L.D.W., also hold stock options in Alnylam Pharmaceuticals. M.G.S., is a principal investigator for clinical studies from Novartis, Gilead, Pliant, Cymabay, Genfit, Target PharmaSolutions. Z.G.J., consults for Olix Pharmaceuticals and receives grants from Gilead Sciences and Pfizer Pharmaceuticals. M.P.C., consults for Mallinckrodt LLC, Alexion Pharmaceuticals, and Albireo Pharma and has also received grants from Sonic Incytes. M.H.C., has received grant support from Bayer. S.V., served as consultant for Albireo Pharma. The other authors do not report any potential conflict of interest. (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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