Clinical utility of genomic analysis in adults with idiopathic liver disease
Open accessAbstract
Background & aims Adult patients suffering from liver disease of unknown cause represent an understudied and underserved population. The use of whole-exome sequencing (WES) for the assessment of a broader spectrum of non-oncological diseases, among adults, remains poorly studied. We assessed the utility of WES in the diagnosis and management of adults with unexplained liver disease despite comprehensive evaluation by a hepatologist and with no history of alcohol overuse.Methods We performed WES and deep phenotyping of 19 unrelated adult patients with idiopathic liver disease recruited at a tertiary academic health care center in the US.Results Analysis of the exome in 19 cases identified 4 monogenic disorders in 5 unrelated adults. Patient 1 suffered for 18 years from devastating complications of undiagnosed type 3 familial partial lipodystrophy due to a deleterious heterozygous variant in PPARG. Molecular diagnosis enabled initiation of leptin replacement therapy with subsequent normalization of liver aminotransferases, amelioration of dyslipidemia, and decreases in daily insulin requirements. Patients 2 and 3 were diagnosed with MDR3 deficiency due to recessive mutations in ABCB4. Patient 4 with a prior diagnosis of non-alcoholic steatohepatitis was found to harbor a mitochondrial disorder due to a homozygous pathogenic variant in NDUFB3; this finding enabled initiation of disease preventive measures including supplementation with antioxidants. Patient 5 is a lean patient with hepatic steatosis of unknown etiology who was found to have a damaging heterozygous variant in APOB.Conclusions Genomic analysis yielded an actionable diagnosis in a substantial number (∼25%) of selected adult patients with chronic liver disease of unknown etiology. This study supports the use of WES in the evaluation and management of adults with idiopathic liver disease in clinical practice.Lay summary We performed whole-exome sequencing in 19 adult patients with unexplained liver disease after an unrevealing conventional work-up performed by a hepatologist. In 5 cases, genomic analysis led to a diagnosis and informed treatment and management of the disease. Therefore, we suggest using whole-exome sequencing in the evaluation and management of adults with unexplained liver disease.
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Initial data suggest that individuals with strong family history, early disease onset, or lack of accruing factors may benefit from a comprehensive genetic evaluation that may identify strong genetic determinants of SLD with potential implications for treatment and family counselling.
“Initial data suggest that individuals with a) strong family history, b) early disease onset, or c) lack of accruing factors may bene fi t from a comprehensive genetic evaluation ( e.g. whole-exome sequencing or targeted panel sequencing) that may identify strong genetic determinants of SLD with potential implications for treatment and family counselling. 135,208 -211”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [209]
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Cites
The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data
McKenna, A., Hanna, M., Banks, E., Sivachenko, A., Cibulskis, K., Kernytsky, A., Garimella, K., Altshuler, D., Gabriel, S., Daly, M., et al. (2010) · Genome Research · doi:10.1101/gr.107524.110 · Cited by 27,895 · see citing works
ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data
Wang, K., Li, M., & Hakonarson, H. H. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq603 · Cited by 14,380 · see citing works
Principal components analysis corrects for stratification in genome-wide association studies
Price, A. L., Patterson, N. J., Plenge, R. M., Weinblatt, M. E., Shadick, N. A., & Reich, D. (2006) · Nature Genetics · doi:10.1038/ng1847 · Cited by 10,248 · see citing works
Analysis of protein-coding genetic variation in 60,706 humans
Exome Aggregation Consortium, Lek, M., Karczewski, K. J., Minikel, E. V., Samocha, K. E., Banks, E., Fennell, T., O’Donnell-Luria, A. H., Ware, J. S., Hill, A. J., et al. (2016) · Nature · doi:10.1038/nature19057 · Cited by 9,587 · see citing works
Van der Auwera, G. A., Carneiro, M. O., Hartl, C., Poplin, R., del Angel, G., Levy‐Moonshine, A., Jordan, T., Shakir, K., Roazen, D., Thibault, J., et al. (2013) · Current Protocols in Bioinformatics · doi:10.1002/0471250953.bi1110s43 · Cited by 6,687 · see citing works
A New Initiative on Precision Medicine
Collins, F. S., & Varmus, H. (2015) · New England Journal of Medicine · doi:10.1056/nejmp1500523 · Cited by 5,202 · see citing works
Clinical Whole-Exome Sequencing for the Diagnosis of Mendelian Disorders
Yang, Y., Muzny, D. M., Reid, J. G., Bainbridge, M. N., Willis, A. S., Ward, P. A., Braxton, A. A., Beuten, J., Xia, F., Niu, Z., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1306555 · Cited by 1,954 · see citing works
Dong, C., Wei, P., Jian, X., Gibbs, R. A., Boerwinkle, E., Wang, K., & Liu, X. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu733 · Cited by 1,106 · see citing works
Clinical Exome Sequencing for Genetic Identification of Rare Mendelian Disorders
Lee, H., Deignan, J. L., Dorrani, N., Strom, S. P., Kantarci, S., Quintero‐Rivera, F., Das, K., Toy, T. L., Harry, B., Yourshaw, M., et al. (2014) · JAMA · doi:10.1001/jama.2014.14604 · Cited by 973 · see citing works
The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities
Chong, J. X., Buckingham, K. J., Jhangiani, S. N., Boehm, C., Sobreira, N., Smith, J. D., Harrell, T. M., McMillin, M. J., Wiszniewski, W., Gambin, T., et al. (2015) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2015.06.009 · Cited by 643 · see citing works
Molecular Diagnosis of Infantile Mitochondrial Disease with Targeted Next-Generation Sequencing
Calvo, S. E., Compton, A. G., Hershman, S. G., Lim, S. C., Lieber, D. S., Tucker, E. J., Laskowski, A., Garone, C., Liu, S., Jaffe, D. B., et al. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3003310 · Cited by 476 · see citing works
Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease
Splinter, K., Adams, D. R., Bacino, C. A., Bellen, H. J., Bernstein, J. A., Cheatle-Jarvela, A. M., Eng, C. M., Esteves, C., Gahl, W. A., Hamid, R., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1714458 · Cited by 359 · see citing works
Exome Sequencing and the Management of Neurometabolic Disorders
Tarailo-Graovac, M., Shyr, C., Ross, C. J., Horvath, G. A., Salvarinova, R., Ye, X. C., Zhang, L.-H., Bhavsar, A. P., Lee, J. J. Y., Drögemöller, B. I., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1515792 · Cited by 281 · see citing works
Murphy, S. L., Xu, J., Kochanek, K. D., Curtin, S. C., & Arias, E. (2017) · PubMed · Cited by 277 · see citing works
Whole-Exome Sequencing in Adults With Chronic Kidney Disease
Lata, S., Marasà, M., Li, Y., Fasel, D. A., Groopman, E., Jobanputra, V., Rasouly, H. M., Mitrotti, A., Westland, R., Verbitsky, M., et al. (2018) · Annals of Internal Medicine · doi:10.7326/m17-1319 · Cited by 207 · see citing works
Phenotypic spectrum and diagnostic pitfalls of ABCB4 deficiency depending on age of onset
Schatz, S. B., Jüngst, C., Keitel, V., et al. (2018) · Hepatology Communications · doi:10.1002/hep4.1149 · Cited by 97 · see citing works
Vilarinho, S., Sarı, S., Mazzacuva, F., Bilgüvar, K., Esendağlı‐Yılmaz, G., Jain, D., Akyol, G., Dalgıç, B., Günel, M., Clayton, P. T., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1613228113 · Cited by 96 · see citing works
Self-citationTarugi, P., Lonardo, A., Gabelli, C., et al. (2001) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)32208-2 · Cited by 65 · see citing works
Seidelmann, S. B., Smith, E., Subrahmanyan, L., et al. (2017) · Circulation Cardiovascular Genetics · doi:10.1161/circgenetics.116.001573 · Cited by 64 · see citing works
Vilarinho, S., Choi, M., Jain, D., Malhotra, A., Kulkarni, S., Pashankar, D. S., Phatak, U. P., Patel, M., Bale, A. E., Mane, S., et al. (2014) · Journal of Hepatology · doi:10.1016/j.jhep.2014.06.038 · Cited by 56 · see citing works
Self-citationCryptogenic Chronic Hepatitis and Its Changing Guise in Adults
Czaja, A. J. (2011) · Digestive Diseases and Sciences · doi:10.1007/s10620-011-1769-9 · Cited by 51 · see citing works
Vilarinho, S., Erson-Omay, Z., Harmancı, A. S., Morotti, R. A., Carrión-Grant, G., Baranoski, J. F., Knisely, A. S., Ekong, U. D., Emre, S., Yasuno, K., et al. (2014) · Journal of Hepatology · doi:10.1016/j.jhep.2014.07.003 · Cited by 51 · see citing works
Self-citationRinaldi, L., Nascimbeni, F., Giordano, M., Masetti, C., Guerrera, B., Amelia, A., Fascione, M. C., Ballestri, S., Romagnoli, D., Zampino, R., et al. (2017) · World Journal of Gastroenterology · doi:10.3748/wjg.v23.i8.1458 · Cited by 51 · see citing works
Alston, C. L., Howard, C., Oláhová, M., et al. (2016) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2015-103576 · Cited by 40 · see citing works
Hepatosteatosis with hypobetalipoproteinemia.
Sen, D. O., Dağdelen, S., & Erbas, T. A. (2007) · PubMed · Cited by 17 · see citing works
Rimbert, A., Pichelin, M., Lecointe, S., et al. (2016) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2016.04.010 · Cited by 16 · see citing works
Pioneering a Global Cure for Chronic Hepatitis C Virus Infection
Vilarinho, S., & Lifton, R. P. (2016) · Cell · doi:10.1016/j.cell.2016.08.038 · Cited by 11 · see citing works
Self-citationFamilial partial lipodystrophy type 3: a new mutation on the PPARG gene
Lau, E., Carvalho, D. M., Oliveira, J., et al. (2015) · HORMONES · doi:10.14310/horm.2002.1585 · Cited by 9 · see citing works
Novel mutation in progressive familial intrahepatic cholestasis III
Chinnaratha, M. A., Venugopal, K., de Boer, W. B., et al. (2013) · Liver International · doi:10.1111/liv.12174 · Cited by 1 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Tacke, F., Horn, P., Wai-Sun Wong, V., Ratziu, V., Bugianesi, E., Francque, S., Zelber-Sagi, S., Valenti, L., Roden, M., Schick, F., et al. (2024) · Journal of Hepatology · doi:10.1016/j.jhep.2024.04.031 · Cited by 2,210 · see citing works
Update on NAFLD genetics: From new variants to the clinic
Trépo, E., & Valenti, L. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2020.02.020 · Cited by 393 · see citing works
Emerging role of genomic analysis in clinical evaluation of lean individuals with NAFLD
Vilarinho, S., Ajmera, V., Zheng, M., & Loomba, R. (2021) · Hepatology · doi:10.1002/hep.32047 · Cited by 85 · see citing works
Self-citationAdvancing diagnosis and management of liver disease in adults through exome sequencing
Zheng, M., Hakim, A., Konkwo, C., Deaton, A. M., Ward, L. D., Silveira, M. G., Assis, D. N., Liapakis, A., Jaffe, A., Jiang, Z. G., et al. (2023) · EBioMedicine · doi:10.1016/j.ebiom.2023.104747 · Cited by 34 · see citing works
Self-citationClinical exome sequencing for diagnosing severe cryptogenic liver disease in adults: a case series
Pelusi, S., Ronzoni, L., Malvestiti, F., Bianco, C., Marini, I., D'Ambrosio, R., Giannotta, J. A., Soardo, G., Maggioni, M., Prati, D., et al. (2022) · Liver International · doi:10.1111/liv.15185 · Cited by 18 · see citing works
Sarabhai, T., Kahl, S., Gancheva, S., Mastrototaro, L., Dewidar, B., Pesta, D., Ratter-Rieck, J. M., Bobrov, P., Jeruschke, K., Esposito, I., et al. (2024) · Metabolism · doi:10.1016/j.metabol.2023.155762 · Cited by 9 · see citing works
Retracted
- Authors
- Hakim, A., Zhang, X., DeLisle, A., Oral, E. A., Dykas, D., Drzewiecki, K., Assis, D. N., Silveira, M., Batisti, J., Jain, D., Bale, A., Mistry, P. K., & Vilarinho, S.
- Affiliations
- Yale University (US)
- University of Michigan (US)
- ORCID
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2019-06
- Volume
- 70
- Issue
- 6
- Pages
- 1214-1221
- ISSN
- 0168-8278 (ISSN-L)
- PMC
- PMC6526061
- OpenAlex
- W2936500884
- Cited by
- 81
- References
- 29
- Citations by year
- 2026: 15 · 2025: 9 · 2024: 11 · 2023: 15 · 2022: 9 · 2021: 7 · 2020: 10 · 2019: 5
- FWCI
- 4.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Hepatology (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR001863)
- National Institute of Diabetes and Digestive and Kidney Diseases (K08DK113109, P30DK020572, P30DK034989)
- National Center for Advancing Translational Sciences
- Yale Liver Center
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- exome sequencing, PPARγ, ABCB4, mitochondrial disease, nonalcoholic steatohepatitis, apolipoprotein B, hepatic steatosis, molecular diagnosis, deep phenotyping, leptin replacement therapy, antioxidants
- MeSH terms
- Exome Sequencing, Adult, Aged, Cholestasis, Intrahepatic, Female, Humans, Liver Diseases, Male, Middle Aged, ATP Binding Cassette Transporter, Subfamily B, Genomics, PPAR gamma, Lipodystrophy, Familial Partial
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