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Review
. 2024 Mar 29;8(4):e0408.
doi: 10.1097/HC9.0000000000000408. eCollection 2024 Apr 1.

Genetics of liver disease in adults

Chigoziri Konkwo  1 , Shanin Chowdhury  1   2 , Silvia Vilarinho  1   2
Affiliations
Review

Genetics of liver disease in adults

Chigoziri Konkwo et al. Hepatol Commun. .

Abstract

Chronic liver disease stands as a significant global health problem with an estimated 2 million annual deaths across the globe. Combining the use of next-generation sequencing technologies with evolving knowledge in the interpretation of genetic variation across the human genome is propelling our understanding, diagnosis, and management of both rare and common liver diseases. Here, we review the contribution of risk and protective alleles to common forms of liver disease, the rising number of monogenic diseases affecting the liver, and the role of somatic genetic variants in the onset and progression of oncological and non-oncological liver diseases. The incorporation of genomic information in the diagnosis and management of patients with liver disease is driving the beginning of a new era of genomics-informed clinical hepatology practice, facilitating personalized medicine, and improving patient care.

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Conflict of interest statement

Silvia Vilarinho served as a consultant to Albireo Pharma, Inc., and receives research grant support from Moderna Therapeutics, Inc. The remaining authors have no conflicts to report.

Figures

FIGURE 1
FIGURE 1
Schematic representation of the contribution of rare (minor allele frequency less than or equal to 1%) genetic variants to monogenic liver diseases, and more frequent genetic variants as risk or protective alleles to common (polygenic) forms of liver disease. Illustrative examples are mentioned. NGS technologies can be used to identify variants across the allele frequency spectrum, while conventional GWAS using genotype arrays only identify common variants associated with disease. However, GWAS are increasingly using WES and WGS data, allowing the identification of both rare and common genetic variants that confer risk for or protection from disease. Abbreviations: GWAS, genome-wide association study; MASLD, metabolic dysfunction–associated steatotic liver disease; NGS, next-generation sequencing; PSVD, porto-sinusoidal vascular disease; SLD, steatotic liver disease; WES, whole-exome sequencing; WGS, whole-genome sequencing.
FIGURE 2
FIGURE 2
Framework for considering and incorporating genetic testing into the evaluation and management of patients with liver disease. Hepatologists may consider obtaining the PNPLA3 p.I148M genotype for individuals with MASLD to assess their risk for progression to advanced liver disease. In cases of unexplained liver disease despite a thorough workup, genomic analysis is recommended as the next step, and referral to a hepatologist with expertise in human genetics or a clinical geneticist may be beneficial. *If there is strong suspicion for a specific group of genetic liver diseases (eg, cholestasis, iron overload, cystic liver/kidney disease, etc.), TGS for a relevant gene panel may be considered. Otherwise, unbiased WES should be considered. For patients diagnosed with HCA, referral to molecular genetic pathology for liver tumor molecular profiling is advised to guide further management. Abbreviations: HCA, hepatocellular adenoma; MASLD, metabolic dysfunction–associated steatotic liver disease; TGS, targeted gene sequencing; WES, whole-exome sequencing.
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