Clinical exome sequencing for diagnosing severe cryptogenic liver disease in adults: a case series
Abstract
Liver diseases remain unexplained in up to 30% of adult patients; genetic analysis could help establish the correct diagnosis. In six adult patients with cryptogenic liver disease, we performed whole-exome sequencing (WES) and evaluated the individual predisposition to progressive fatty liver disease by polygenic risk scores (PRS). In one patient, WES was allowed to diagnose the Hermansky-Pudlak syndrome. In the other two patients, genetic variants in LDLRAP1/MSH6 and ALDOB genes were identified, contributing to explaining the clinical presentation and disease pathogenesis (50% diagnostic uptake). In the other three patients, rare variants with a high likelihood of disrupting protein function in APOB, ATP7B, ABCB4 and ATP8B1 were identified. One patient who developed hepatocellular carcinoma during the follow-up had a high PRS value. The study supports the role of WES, combined with risk stratification by PRS and accurate clinical assessment in improving the diagnosis and informed management in patients with cryptogenic liver disease, a positive family history or severe fatty liver not fully accounted for by environmental triggers.
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Using next generation sequencing, a refined diagnosis such as monogenic SLD can currently be reached in up to one-third of individuals.
“Using next generation sequencing (NGS), a re fi ned diagnosis ( e.g. monogenic SLD) can currently be reached in up to onethird of individuals. 208,210,212”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [210]
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 [210]
Cites
The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome
Lim, J. S., Mietus-Snyder, M., Valente, A., Schwarz, J.-M., & Lustig, R. H. (2010) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2010.41 · Cited by 771 · 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
Bianco, C., Jamialahmadi, O., Pelusi, S., Baselli, G., Dongiovanni, P., Zanoni, I., Santoro, L., Maier, S., Liguori, A., Meroni, M., et al. (2021) · Journal of Hepatology · doi:10.1016/j.jhep.2020.11.024 · Cited by 385 · see citing works
Dongiovanni, P., Stender, S., Pietrelli, A., Mancina, R. M., Cespiati, A., Petta, S., Pelusi, S., Pingitore, P., Badiali, S., Maggioni, M., et al. (2018) · Journal of Internal Medicine · doi:10.1111/joim.12719 · Cited by 367 · see citing works
Rare pathogenic variants predispose to hepatocellular carcinoma in nonalcoholic fatty liver disease
Pelusi, S., Baselli, G., Pietrelli, A., Dongiovanni, P., Donati, B., McCain, M. V., Meroni, M., Fracanzani, A. L., Romagnoli, R., Petta, S., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-39998-2 · Cited by 125 · see citing works
Self-citationMolecular overview of progressive familial intrahepatic cholestasis
Amirneni, S., Haep, N., Gad, M. A., Soto–Gutiérrez, A., Squires, J. E., & Florentino, R. M. (2020) · World Journal of Gastroenterology · doi:10.3748/wjg.v26.i47.7470 · Cited by 93 · 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
ABCB4 gene aberrations in human liver disease: an evolving spectrum
Reichert, M., & Lammert, F. (2018) · Seminars in Liver Disease · doi:10.1055/s-0038-1667299 · Cited by 81 · see citing works
Clinical utility of genomic analysis in adults with idiopathic liver disease
Hakim, A., Zhang, X., DeLisle, A., Oral, E. A., Dykas, D., Drzewiecki, K., Assis, D. N., Silveira, M., Batisti, J., Jain, D., et al. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2019.01.036 · Cited by 81 · see citing works
Liu, G., Wang, N., Zhang, C., Li, M., He, X., Yin, C., Tu, Q., Shen, X., Zhang, L., Lv, J., et al. (2021) · Hepatology · doi:10.1002/hep.32064 · Cited by 61 · see citing works
Non-alcoholic fatty liver in hereditary fructose intolerance
Aldamiz-Echevarria, L. J., Heras, J. D. L., Couce, M. L., Alcalde, C. L., Vitoria, I., Bueno, M. A., Blasco‐Alonso, J., García, M. C., Ruiz, M., Carrero, R. S. D. V., et al. (2019) · Clinical Nutrition · doi:10.1016/j.clnu.2019.02.019 · Cited by 47 · see citing works
Exome Sequencing in Clinical Hepatology
Vilarinho, S., & Mistry, P. K. (2019) · Hepatology · doi:10.1002/hep.30826 · Cited by 34 · see citing works
Fahed, A. C., Khalaf, R. I., Salloum, R. H., Andary, R. R., Safa, R., El‐Rassy, I., Moubarak, E. M., Azar, S. T., Bitar, F. F., & Nemer, G. M. (2016) · Molecular Genetics & Genomic Medicine · doi:10.1002/mgg3.203 · Cited by 23 · see citing works
APOB-Related Familial Hypobetalipoproteinemia
Burnett, J. R., Hooper, A. J., & Hegele, R. A. (2021) · Europe PMC (PubMed Central) · Cited by 21 · see citing works
Piazzolla, M., Castellaneta, N. M., Novelli, A., Agolini, E., Cocciadiferro, D., Resta, L., Duda, L., Barone, M., Ierardi, E., & Leo, A. D. (2020) · World Journal of Hepatology · doi:10.4254/wjh.v12.i2.64 · Cited by 18 · see citing works
Familial Hypobetalipoproteinemia: An Underrecognized Cause of Lean NASH
Buryska, S. M., Ahn, J. C., Allen, A. M., Simha, V., & Simonetto, D. A. (2021) · Hepatology · doi:10.1002/hep.31988 · Cited by 14 · see citing works
Long, J., Bian, J., & Zhao, H. (2021) · Journal of Hepatology · doi:10.1016/j.jhep.2021.01.010 · Cited by 12 · see citing works
Individualized medicine comes to the liver clinic
Vairo, F. P. E., & Lazaridis, K. N. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2019.03.025 · Cited by 9 · see citing works
Whole exome sequencing for personalized hepatology: Expanding applications in adults and challenges
Valenti, L. V. C., Pelusi, S., & Baselli, G. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2019.06.008 · Cited by 7 · 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
(2024) · Obesity Facts · doi:10.1159/000539371 · Cited by 510 · see citing works
The contribution of genetics and epigenetics to MAFLD susceptibility
Moretti, V., Romeo, S., & Valenti, L. V. C. (2024) · Hepatology International · doi:10.1007/s12072-024-10667-5 · Cited by 43 · see citing works
Zheng, M., Huang, D. Q., Konkwo, C., Agrawal, S., Khera, A. V., Loomba, R. S., Vilarinho, S., & Ajmera, V. H. (2023) · JHEP Reports · doi:10.1016/j.jhepr.2023.100692 · Cited by 26 · see citing works
The genetics of portal hypertension: Recent developments and the road ahead
Shalaby, S., Ronzoni, L., Hernández–Gea, V., & Valenti, L. V. C. (2023) · Liver International · doi:10.1111/liv.15732 · Cited by 13 · see citing works
The diagnostic yield of exome sequencing in liver diseases from a curated gene panel
Kong, X., Bogyo, K., Kapoor, S., Shea, P. R., Groopman, E., Thomas‐Wilson, A., Cocchi, E., Rasouly, H. M., Zheng, B., Sun, S., et al. (2023) · Scientific Reports · doi:10.1038/s41598-023-42202-1 · Cited by 9 · see citing works
African genetic ancestry and protection against fatty liver disease
Romeo, S., & Valenti, L. V. C. (2022) · Liver International · doi:10.1111/liv.15364 · Cited by 9 · see citing works
Diagnostic Yield of Whole Exome Sequencing in Adult-onset Cholestatic Liver Disease
Scaravaglio, M., Ronzoni, L., Cristoferi, L., Miano, L., Nofit, E., Gerussi, A., Malinverno, F., Moretti, V., Torcianti, V., Caime, C., et al. (2025) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2025.07.031 · Cited by 8 · see citing works
Genetics: A new clinical tool for the hepatologist
Valenti, L. V. C., & Ronzoni, L. (2022) · Liver International · doi:10.1111/liv.15205 · Cited by 8 · see citing works
Whole‐exome sequencing for genetic diagnosis of idiopathic liver injury in children
Lülecioğlu, A. A., Yazıcı, Y. Y., Baran, A., Warasnhe, K., Beyaz, Ş., Aytekin, C., Özçay, F., Aydemir, Y., Barış, Z., & Belkaya, S. (2024) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.18485 · Cited by 6 · see citing works
Ronzoni, L., Marini, I., Passignani, G., Malvestiti, F., Marchelli, D., Bianco, C., Pelusi, S., Prati, D., & Valenti, L. V. C. (2023) · Frontiers in Genetics · doi:10.3389/fgene.2023.1137016 · Cited by 5 · see citing works
Ronzoni, L., Mureddu, M., Malvestiti, F., Moretti, V., Bianco, C., Periti, G., Baldassarri, M., Ariani, F., Carrer, A., Pelusi, S., et al. (2023) · Genes · doi:10.3390/genes14081633 · Cited by 5 · see citing works
Ronzoni, L., Pelusi, S., Moretti, V., Malvestiti, F., Torghabehei, H. E., Jamialahmadi, O., Rondena, J., Bianco, C., Periti, G., Filippo, M. R. D., et al. (2025) · Liver International · doi:10.1111/liv.70010 · Cited by 3 · see citing works
Exome Sequencing in Adults with Unexplained Liver Disease: Diagnostic Yield and Clinical Impact
Moral, K., Kayhan, G., Duzenli, T., Sarı, S., Cindoruk, M., & Ekmen, N. (2025) · Diagnostics · doi:10.3390/diagnostics15162010 · Cited by 2 · see citing works
Ronzoni, L., Pietro, G. M. D., Lombardi, A., Miano, L., Minoia, F., Baselli, L. A., Filocamo, G., Torcianti, V., Malvestiti, F., Bosis, S., et al. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1777516 · Cited by 2 · see citing works
Challenges associated with diagnostic exome sequencing in liver diseasesPreprint
Kong, X., Bogyo, K., Kapoor, S., Groopman, E., Thomas‐Wilson, A., Cocchi, E., Rasouly, H. M., Zheng, B., Sun, S., Zhang, J., et al. (2022) · medRxiv · doi:10.1101/2022.06.21.22276400 · Cited by 1 · see citing works
Boppana, S. H., Luke, N., Karuchola, S., Udaikumar, J., & Mintz, C. D. (2026) · Pharmaceutics · doi:10.3390/pharmaceutics18040455
Genetic testing in liver diseases: Clinical applications
Keitel, V., Mentzinger, A., Dröge, C., & Vilarinho, S. (2026) · JHEP Reports · doi:10.1016/j.jhepr.2026.101902
- Authors
- Pelusi, S., Ronzoni, L., Malvestiti, F., Bianco, C., Marini, I., D'Ambrosio, R., Giannotta, J. A., Soardo, G., Maggioni, M., Prati, D., & Valenti, L.
- Affiliations
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
- University of Milan (IT)
- Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano Milan Italy
- University of Udine (IT)
- Corresponding author
- Ronzoni, Luisa
- ORCID
- Venue
- Liver International
- Publisher
- Wiley
- Published
- 2022-02-15
- Volume
- 42
- Issue
- 4
- Pages
- 864-870
- ISSN
- 0106-9543 (ISSN-L)
- 1478-3223
- 1478-3231
- OpenAlex
- W4210908320
- Cited by
- 18
- References
- 19
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 4 · 2023: 5 · 2022: 3
- FWCI
- 2.71
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Liver International (publishedVersion)
- PubMed (publishedVersion)
- Institutional Research Information System (University of Udine) (submittedVersion)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- cryptogenic liver disease, exome sequencing, genetic diagnosis, polygenic risk score, Hermansky-Pudlak syndrome, LDLRAP1, MSH6, aldolase B, apolipoprotein B, ATP7B, ABCB4, ATP8B1, hepatocellular carcinoma, rare variants, adults
- MeSH terms
- Exome Sequencing, Adult, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Mutation, Exome
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