Hepatology Genome Rounds: An interdisciplinary approach to integrate genomic data in clinical practice

SUMMARY

In the last decade, whole-exome sequencing has successfully demonstrated its utility in uncovering genetic etiologies of a variety of liver diseases. These new diagnoses have allowed clinicians to guide heretofore undiagnosed patients on management, treatment, and prognosis largely due to improved insight into the underlying pathogenesis. Despite its clear benefits, genetic testing has had limited uptake by hepatologists, in part due to limited prior genetic training and/or opportunities for continuing education. Here, we discuss that Hepatology Genome Rounds, an interdisciplinary forum highlighting hepatology cases of clinical interest and educational value, are an important venue for integrating genotype and phenotype information for proper patient diagnosis and management, for dissemination of genomic knowledge within the field of hepatology, and for providing ongoing education to providers and trainees in genomic medicine. We describe our single-center experience and discuss practical considerations for clinicians interested in launching such a series. We foresee that this format will be adopted at other institutions and in additional specialties for further incorporation of genomic information in clinical medicine.

Advances in next-generation sequencing technologies have revolutionized the delineation of clinical syndromes in the past two decades. Specifically, incorporation of whole-exome and whole-genome sequencing (WES and WGS, respectively) into clinical practice across multiple medical subspecialties has underpinned a transformation in genetic diagnosis, characterization of disease mechanisms, understanding of genotype-phenotype correlation, and consequently prognostication and identification of novel therapeutic targets.

In the field of hepatology, the utility of genomic analysis continues to emerge, with increasing use of WES to successfully diagnose unexplained liver disease in both adult and pediatric populations.(1, 2) These discoveries have elucidated the foundations of heretofore unexplained phenotypes and have allowed management and treatment to be fine-tuned based on an improved understanding of pathophysiology.(1-7) However, genetic analysis has yet to be widely adopted by hepatologists, even as the costs of such analysis have exponentially decreased and evidence of its clinical utility has been demonstrated.(1, 8) Such reluctance is not unique to hepatology and may reflect various factors, including lack of genetic training, poor understanding of when a genetic investigation may be warranted, difficulty in interpreting genetic reports, and preconceived biases that genomic analysis is only useful in children and/or yield too many variants of uncertain significance to make meaningful impact in clinical care of adult patients.(8, 9)

Hence, there is a major unmet need to create forums through which clinicians can gain a better appreciation for the value of genetic analysis and can amass the knowledge and confidence to incorporate genetic analysis into their own clinical practice. To address these needs in hepatology, we initiated a Hepatology Genome Rounds series at our institution. This forum serves as a multidisciplinary conference at which clinical cases of particular interest are discussed through the lens of genomic data.(1, 8) Here, we discuss the broader applicability of Hepatology Genome Rounds in the setting of growing interdisciplinary collaboration across various fields of medicine. We delineate the overarching vision and objectives of the series based on our single-center experience, consider its clinical and educational value among attendings and trainees, and outline practical considerations for academic hepatologists launching such a series at their institution.

Interdisciplinary medicine and its value

Interdisciplinary collaboration across specialties is not a novel concept and has become standard-of-care in several fields. Perhaps the most well-established among this model of clinical care are tumor boards. The congregation of multiple disciplines and modalities in a single forum facilitates disease stratification among common cancers and radiologic-pathologic and clinical correlation in complex and/or atypical cancer cases and promotes expert recommendations, allowing for acceleration and optimization of patient care. In many instances, these discussions yield new insights or clarifications that directly lead to changes in diagnosis and/or medical and surgical management.(10, 11) Though there are minimal data on the eventual impact of tumor boards on patient survival, some institutions have demonstrated improvements in measures of quality of care among patients reviewed within a multidisciplinary context.(12, 13) Complementary to its contributions to clinical care, tumor boards provide academic medical centers with the additional benefit of serving as an educational opportunity for learners at various levels of training.(10) The multidisciplinary tumor board, which brings together clinicians, surgeons, pathologists, and radiologists, has indeed been adopted across numerous oncologic specialties. Thus, while an interdisciplinary forum for genetic contributions to liver disease may be new, hepatologists have already been leading and participating in these joint clinical efforts, such as liver tumor boards.

Cross-collaboration among specialties is gaining traction elsewhere as well, with a similar interdisciplinary format being increasingly utilized in non-oncologic sub-specialties, with direct, measurable impacts on patient care.(14, 15) As accessibility to genetic data has grown, incorporation of genomics into clinical care within a multidisciplinary context has been proposed in several disciplines, including cardiology and hematopathology.(16, 17) Furthermore, as the genetic basis underlying rare and common diseases continues to be better understood, we believe that multiple fields within medicine, beyond hepatology, will likely benefit from the introduction of a multidisciplinary forum similar to that described herein to discuss challenging and/or undiagnosed cases and to advance patient care.

Hepatology genome rounds: vision and goals

Our Hepatology Genome Rounds series was launched with the vision that individual genomic analysis and its review and discussion in a multidisciplinary forum would assist in understanding why an individual develops chronic liver disease, facilitating optimal patient management and prognostication. Its execution will lead to the achievement of at least five overarching goals, such as (i) developing best practice clinical guidance for the application of genomic analysis in the evaluation and management of liver disease; (ii) generating new genotype-phenotype knowledge; (iii) promoting the delivery of excellent clinical care in the field of hepatology; (iv) fostering scientific inquiry in trainees and colleagues; and (v) providing up-to-date information and education in genomic medicine for liver disease (Box 1).(1, 8)

Box 1. Key five overarching goals of Hepatology Genome Rounds series.

1. Develop best clinical practice guidance for application of genomic analysis in the evaluation and management of liver disease.

2. Generate new genotype-phenotype knowledge.

3. Foster scientific inquiry in trainees and colleagues.

4. Promote the delivery of excellent clinical care in the field of hepatology.

5. Provide up-to-date information and education in genomic medicine for liver disease.

These discussions allow hepatologists, clinical geneticists, pathologists, and other health care providers to sharpen their clinical acumen and gain additional insight into ways in which their contributions to patient care can be maximized. For instance, they present an opportunity for clinical geneticists to receive feedback on what may be relevant to clinicians at the receiving end of genetic reports. This is important not only given the varying proficiency with genetic analysis among providers, but also for improved interdisciplinary collaboration in the clinical setting. Furthermore, by reviewing liver biopsy findings alongside clinicians and geneticists, pathologists can hone their ability to determine when it may be appropriate to suggest genomic analysis to clinicians, especially in specific cases of idiopathic liver disease.(1, 8, 18)

Such forums also have the potential to become important platforms for patient advocacy. For example, only a small fraction of individuals with a history of alcohol use develops chronic liver disease, and genetic variants can contribute to progression of chronic liver disease. Similarly, individuals evaluated in fatty liver disease/obesity clinics may harbor melanocortin 4 receptor mutations, for which new therapies can be considered. Facile labelling of diagnoses such as alcoholic liver disease or obesity can cause profound stigma and lead that such individuals being underserved by the healthcare system. Longitudinal education on such genetic underpinnings will encourage holistic evaluation of all patients and challenge existing cognitive biases and heuristics in clinical medicine.

Practical advice for the academic hepatologist

First, we envision the Hepatology Genome Rounds series taking place in academic medical centers with solid technical and analytical expertise in cutting-edge genetic diagnostic technology and a strong hepatology community with deep knowledge in liver phenotypes. This is similar to how liver transplantation is not offered at every medical center due to the requisite expertise. At our institution, the Hepatology Genome Rounds series constitutes one component of a larger Undiagnosed Liver Disease Program, which also houses an undiagnosed liver disease clinic, provides consultation on rare and atypical hepatology cases, and benefits from an NIH-funded basic and translational research laboratory.

Second, while a hepatologist will be expected to lead the series featuring hepatology cases as it occurs in liver tumor boards, its success and sustainability will only be possible if executed as a joint effort among participating specialists, in particular clinical geneticists, and liver pathologists. As genetic data continues to grow at a near-exponential rate, clinical geneticists, in isolation, may understandably not be able to integrate all the genotypic information available for a disorder due to disease heterogeneity and phenotypic expansion. Hence, collaborative efforts with experts in different subspecialties, including hepatology, is the way forward for effective and timely patient care.

Third, both community and academic hepatologists play a key role in expanding the reach and impact of Hepatology Genome Rounds. It is important that hepatologists identify patients who may benefit from comprehensive genetic analysis and refer them to centers that have this expertise. This mirrors the current evaluation process for liver transplantation and/or initiation of complex therapies. General hepatologists thus play a critical role in shortening the time between clinical presentation and genomic analysis, by referring the right patient to the appropriate specialized centers. Fortunately, the objectives of Hepatology Genome Rounds can be self-fulfilling. It not only serves as an educational opportunity in which general hepatologists can present their patient(s) and remain up to date on genomic principles in hepatology, but also constitutes a multidisciplinary forum of expert physicians to which general hepatologists may subsequently consult and/or refer their patients as appropriate.

Fourth, once the framework for the series is established, the final piece in its launch is the identification of appropriate patients for discussion. Targeted gene panels for certain liver disease presentations, such as cholestatic liver disease or polycystic liver disease, are commercially available. Thus, if clinical suspicion for a specific disease (e.g., Alagille syndrome, MDR3 deficiency) is high, these should be pursued. However, if targeted gene panel testing is negative or an individual has an atypical phenotype, further evaluation using WES will likely be beneficial in attaining a diagnosis or ruling out most known genetic causes for the clinical presentation.(19) Based on emergent data, criteria have been proposed for which patients with liver disease merit further analysis with WES.(1, 20, 21) We expect these criteria to be further refined as additional data from larger and follow-up studies on application of genomic analysis to different presentations of undiagnosed liver disease become available. It is estimated that WES will successfully yield a diagnosis in approximately 50-80% of newborns and 25-50% adult patients with late-onset phenotypes.(22-25) In some patients, WES does not provide a definitive diagnosis, but reveals rare variants, which may not fulfill strict criteria to be classified as pathogenic or benign and therefore are designated as “variants of uncertain significance” (VUS). These VUSs are a common feature in genetic test reports, and their interpretation benefits from correlation within the entire clinical context of a patient.(1, 26-28) By facilitating a multi-pronged, comprehensive analysis of genotypic and phenotypic data, our Hepatology Genome Rounds series allows providers and trainees to collectively discuss a patient’s clinical presentation and arrive at, revisit, and/or refine a patient’s diagnosis, with the goal of subsequently optimizing management, treatment, prognosis, and family counseling (Figure 1). While the discussion largely revolves around rare variants suspected of causing disease, common variants associated with the clinical presentation (e.g., the polymorphism p.I148M in PNPLA3 in a patient with hepatic steatosis) should be included in the holistic review of the patient, especially with respect to their potential effects on amplifying or mitigating the disease process and phenotype. Numerous resources are currently publicly available to clinicians to assist in this process of gene-disease relationship and genotype-phenotype correlation (Table 1).

Figure 1.

Schematic diagram depicting the incorporation of Hepatology Genome Rounds in the evaluation of patients with atypical or unexplained liver disease. Dashed line indicates ‘certain cases’.

Table 1.

Overview of key genomics tools and resources for genotype-phenotype correlation and gene-liver disease relationship.

Type	Utility	Resource	Website
Exome and Genome Sequencing Database	Assess minor allele frequency of a genetic variant across populations	Genome Aggregation Database (gnomAD)	https://gnomad.broadinstitute.org/
Genome Browser	Assess gene annotations, isoforms	Ensembl	https://ensembl.org/
		UCSC Genome Browser	https://genome.ucsc.edu/
Human Gene Database	Provide information about a specific gene	GeneCards	https://www.genecards.org/
		UniProt	https://www.uniprot.org/
Gene-Disease Relationship Database	Assess whether a gene alteration has been reported as the cause of a human disease	Online Mendelian Inheritance in Man (OMIM)	https://omim.org/
Genotype-Phenotype Correlation	Assess whether a genetic variant has been annotated for pathogenicity	ClinVar	https://www.ncbi.nlm.nih.gov/clinvar/

Fifth, new insights gained within the Hepatology Genome Rounds series should be publicized for the benefit of the medical community at large and in turn our patients. Hepatologists can work with clinical geneticists in determining the appropriateness of pathogenicity classifications and uploading new variants or modifications to previous annotations to databases. Pathogenicity classification is admittedly a circuitous task,(29) and a more reproducible and accurate determination will likely result from close collaboration with our colleagues and wide application of individual WES to patients with liver disease. Publication of detailed genotypic and phenotypic information of these patients in peer-reviewed journals further buttresses this work and will facilitate dissemination of novel information that could aid other clinicians in the field. This practice will ultimately result in increased clarity and robust genetic variant classification.

Lastly, for patients in whom WES does not produce any actionable variants, reanalysis of the exome is indicated every 1-2 years,(30-32) given the rapid growth in available genetic data, updates to human genome alignment, variant calling, and annotation programs, human liver single cell atlases(33, 34), and new genetic variant classification and genotype-phenotype correlation information by other laboratories.(35) If VUSs or heterozygous variants in genes associated with recessive diseases(28) result from reanalysis, these cases should undergo clinical correlation in Hepatology Genome Rounds (Figure 1). Alternatively, WGS may be considered to look for genetic diseases beyond the scope of WES, such as those caused by structural variants or genetic variants in noncoding regions. WGS has been effectively used for diagnosis following nondiagnostic WES in other fields, and the additional diagnostic rate from WGS versus WES appears to be about 5-10% across diagnoses. However, data on the role of WGS in liver disease diagnosis is still not available. If the etiology of disease remains unresolved upon such further investigation, providers should return to a holistic clinical assessment of the patient and reconsider non-genetic liver diseases.

A single-center experience: an early review

Our Hepatology Genome Rounds series, which was initiated at our center in early 2021, represents a collaborative effort among adult and pediatric gastroenterology and hepatology, pathology, and clinical genetics. We have completed eleven sessions, and each of them featured an individual clinical case. Along with a discussion of the patient’s clinical presentation, WES results, and liver biopsy findings, the conferences were framed to convey specific learning objectives highlighting themes central to the field of genomic medicine. These sessions proved a diverse setting, with attendees ranging from attending physicians to fellows, genetic counselors, medical students, and basic researchers, with varying levels of expertise in genetic analysis.

An illustrative example is a case which has previously been described.(1) A 31-year-old woman, with a past medical history notable for intrahepatic cholestasis of pregnancy (ICP) during her first pregnancy, presented with esophageal variceal hemorrhage during her second pregnancy. Following her first pregnancy, she had undergone extended gene analysis and was found to harbor a heterozygous missense variant in ABCB4 (NM_000443.4:c.1645C>T; p.R549C). At that time, the patient was diagnosed with ICP, which can result from a rare loss-of-function heterozygous variant in ABCB4, because the variant was predicted to be deleterious, and a different amino acid substitution at the same position (p.R549H) was associated with ICP in the literature.(36) However, when the patient presented during her second pregnancy with hematemesis secondary to esophageal variceal hemorrhage and was found to have high gamma-glutamyltransferase cholestasis, with liver biopsy demonstrating cirrhosis, the patient’s genetic data was re-analyzed within the context of her evolving phenotype (Figure 1). Notably, a variant, which had initially been classified as a VUS (ABCB4:NM_000443.4:c.2800G>A; p.A934T) and had not been reported due to a minor allele frequency (MAF) slightly above the cut-off of 1%, was re-considered due to data demonstrating that this variant results in a significant decrease in protein level and function,(37) as well as its classification as a likely pathogenic variant by a number of laboratories. Considering the developments in phenotype and genetic knowledge, the patient was diagnosed with MDR3 deficiency, with an autosomal recessive mode of inheritance, due to bi-allelic loss-of-function mutations in ABCB4, consistent with other reports of MDR3 deficiency diagnosed in adulthood.(38) While newly approved therapies for MDR3 deficiency are not indicated in patients with decompensated cirrhosis, this diagnostic clarification will allow for accelerated optimization of care should new therapeutics emerge or indication for current therapies expand, and provides assurance that liver transplantation will be curative.

This case underscores the importance of interpreting genetic results alongside an understanding of the entire clinical context of a patient and highlights the importance of reanalyzing genetic data in the setting of evolving phenotypic features. This process resembles the well-accepted iterative process in internal medicine practice of re-interpreting imaging studies with radiologists or reviewing biopsy slides with pathologists when previously unappreciated clinical information becomes available. Overall, genetic results are no different than other diagnostic tests, which require clinical correlation and re-analysis in certain circumstances.

While sessions in our inaugural Hepatology Genome Rounds series thus far have been largely educational, providing a review of recent cases within our institution, we envision that this interdisciplinary forum will evolve to support real-time cases in which cross-disciplinary collaboration allows for timely changes in diagnosis and management of patients with liver disease. To date, the spirited discussions have already yielded new insights, including reconsideration of diagnoses in two patients and an overall improved understanding of genotype-phenotype correlations across all eleven cases.

Given that the Hepatology Genome Rounds is designed to feature atypical and/or complex cases, the discussions will not always result in a definitive diagnosis or a change in management. However, regardless of the outcome, providers gain a deeper understanding of the nuances of genomic medicine that they can carry forward in their practice. Even when a satisfactory diagnosis cannot be reached, it has been our experience that the series allows providers to collaborate in identifying actionable tasks. These have included carrying out genetic testing in family members, providing regular surveillance care with appropriate specialists, and eliciting the opinion of leading world experts in the specific genetic disease(s) in question. We believe that the development of these action plans is important in providing the best care for our patients and propelling forward our knowledge of disease. As we continue our series, we will share our novel findings through both publications and updates to a centralized database of liver-related genes. The latter is currently in development and will focus on gene-liver disease relationships and genotype-phenotype correlations to fulfill an unmet need in our scientific community.(8)

Genome rounds as a pathway to merge genomic information into routine clinical care

With increasing availability and affordability of genomic analysis, the need to interpret genomic information in the context of a patient’s clinical presentation continues to grow. Through our single-center Hepatology Genome Rounds, we would like to share the utility of establishing an educational venue for various disciplines to come together and correlate multiple points of genotypic and phenotypic information, with the purpose of assessing diagnoses and fine-tuning management in patients with idiopathic liver disease. It is time for the field of hepatology to fully benefit from the incorporation of genomic analysis into clinical practice, and we envision the continued evolution and growth of Hepatology Genome Rounds into a multi-institutional hybrid (virtual and in-person) format for widespread dissemination of clinically relevant genomic knowledge. We also believe that our series has laid the groundwork for similar interdisciplinary genome rounds to sprout in other specialties of medicine for the benefit of future generations of patients.