Advances in human genetics research
Our understanding of human genetics has evolved exponentially since it was first discovered that human traits could be inherited. Today’s human genetics research covers a multitude of topics including the sequencing, annotation, and characterization of the human genome, leveraging multiomic data—including genomic data—for the screening, diagnosis, and treatment of genetic diseases such as cancer, mitochondrial, and neurodegenerative diseases, and the burgeoning field of precision medicine including pharmacogenomics.
The annual European Society of Human Genetics (ESHG) conference is a historic, global meeting of researchers, physicians, genetic counsellors, commercial companies, and graduate students, with registered attendance traditionally numbering in the thousands. ESHG provides a platform for the discourse of recent advances in human genetics and fosters an environment for collaboration and knowledge exchange. This year, the ESHG conference was offered as a hybrid event, taking place both virtually and in-person at the venue in Vienna, Austria from June 11-14, 2022.
If you were unable to attend, below are some of the key themes and takeaways from the conference. The summary below highlights how each theme is important for advancing our current understanding of human genetics and improving healthcare.
Leveraging multiomic data for healthcare
Multiomics, integrative omics, or panomics can be used interchangeably and all refer to a relatively new analysis approach where different types of large-scale biological results are analyzed collectively. Although several types of omic sciences are being used in studies, the most well-known include genomics, proteomics, transcriptomics, and metabolomics. By assessing a biological sample using multiple omics, researchers acquire more comprehensive molecular insight, thus making it easier to decipher underlying mechanisms and pathways impacted in specific diseases.
At this year’s ESHG conference, several offered sessions were on the subject of multiomics with many researchers mentioning how multiomic workflows have benefited their research programs. For example, several genetic disease studies (e.g., muscular, mitochondrial, cancer, etc.) have benefited from the addition of RNA sequencing (i.e., transcriptomics), which complements genomic datasets. Importantly, combining RNA sequencing with genomic data has been shown to increase diagnostic yield in several genetic diseases, including certain neurodevelopmental disorders, as one example.
The improvement seen in diagnostics from the incorporation of RNA sequencing (versus whole exome or whole genome sequencing alone) was the focus of the oral presentation by Dr. Beryl Cummings, senior associate at Third Rock Ventures, San Francisco, U.S.A., titled, “Transcript expression-aware annotation for improved diagnostics”. In her presentation, Dr. Cummings went over several examples where RNA sequencing was used to complement genomic data.
Utilizing genomic data for cancer screening and diagnosis
Numerous presentations given by early (graduate students), post-doctoral, and late-stage researchers at this year’s ESHG conference focused on various types of hereditary cancers (e.g., renal cell, breast, ovarian, diffuse gastric or stomach, colorectal, endometrial, etc.) and how these cancers can be characterized using genomic data.
Acquiring a cancer patient’s genomic information (i.e., sequencing their DNA)—using second or third generation sequencing technologies such as Illumina® Sequencing or Oxford Nanopore Technologies®, respectively—can be used to identify pathogenic germline variants or mutations indicative of hereditary cancer risk. Aside from screening and diagnostic purposes, the identification of such variants can also be useful for determining the best cancer treatment option and management strategy. When multiple, genetic variants are known for a specific type of cancer, they can be assessed collectively to assign a “polygenic risk score”, a numerical value assigned to a patient that estimates the combined effect of the mutations on a patient’s phenotype. The value of using polygenic risk scores for cancer screening was touched on in several presentations; for example, genetic assessments of breast cancer risk that do not include polygenic risk scores often miss a significant number of women at high genetic risk of developing breast cancer.
Many presenters also discussed known cancer susceptibility genes—previously identified genes shown to be mutated or altered in specific cancers (e.g., BRCA1/2 are well-known breast cancer susceptibility genes). Cancer susceptibility genes are frequently part of so-called gene “panels” developed to test and screen for cancer risk. It was emphasized that improving diagnostic yield would only be possible if current gene panel testing for specific cancers was expanded to include additional cancer susceptibility genes and/or by expanding age-based eligibility criteria to undergo panel testing. During the question period for one of the presentations, it was mentioned that in an ideal world, rather than targeted panel approaches, whole genome sequencing would be performed as an all-encompassing screening approach to detect all genetic abnormalities.
Screening options and diagnostics for non-cancer genetic diseases
Similar to the available screening and diagnostic approaches for cancer, several other genetic diseases can be identified and characterized using genomic sequencing approaches (e.g., whole genome or exome sequencing). Several genetic diseases were highlighted at this year’s ESHG conference including metabolic, rare, mitochondrial, congenital, and neurodevelopmental diseases (e.g., PMM2-congenital disorder of glycosylation, Wolf-Hirschhorn syndrome, Costello syndrome, inherited metabolic disorders, Bachmann-Bupp syndrome, Marfan syndrome, VEXAS syndrome, etc.).
In addition, two invited oral presentations highlighted how host genetics can make one vulnerable to infections, including COVID-19 (presented by Dr. Kenneth Bailey from the University of Edinburgh, U.K.) and how next generation sequencing (also known as second generation sequencing) can be used as a diagnostic tool for COVID-19 (presented by Dr. Kerstin Ludwig from the University of Bonn, Germany). These presentations demonstrated that while COVID-19 is not considered a human genetic disease, assessing host genetics and defining the associations between COVID-19 patients’ genotypes and phenotypes can still provide valuable insight into how such diseases may manifest in others.
Implementing reproductive carrier screening—genetic tests that can determine whether an individual and/or their reproductive partner have an increased chance of having a child with an inherited genetic condition—was another major topic covered at this year’s ESHG conference. The primary goal of screening initiatives is to assist potential families in their decision-making. Several barriers, including funding for such initiatives, were also acknowledged.
Looking to the future: precision medicine and pharmacogenomics
Pharmacogenomics (often abbreviated as “PGx”) assesses how variations in an individual’s genetic makeup affect their response to pharmaceutical drugs. Based on our current understanding, pharmacogenomics involves identifying a genetic variant that correlates to a drug reaction, not a predisposition to a particular disease.
A reoccurring theme at this year’s ESHG conference was the implementation and value of pharmacogenomics. At present, the implementation of pharmacogenomics—a growing field of study—has been understandably slow, but the value of this field of research is undeniable. During his invited oral presentation, Dr. Munir Pirmohamed, National Health Service Chair of Pharmacogenomics at the University of Liverpool, U.K., highlighted some key reasons on why we need pharmacogenomics:
Pharmacogenomics addresses the variability people have in their response to drugs and will improve drug efficacy and safety (i.e., presently, most drugs—greater than 90%—only work in 30-50% of people).
Using pharmacogenomics testing allows us to avoid severe and adverse drug reactions in patients. These patients often end up in hospitals and represent a significant burden to healthcare systems, globally.
Later during the conference, a workshop session was held on priorities in pharmacogenomics. Dr. William Newman from the University of Manchester, U.K., delivered two back-to-back oral presentations during the workshop and raised several key points on pharmacogenomics implementation and hurdles. One of the points he raised acknowledged that pharmacogenomics is only one factor in optimizing medication. Other factors include identifying optimal patient dose, improving drug prescription accuracy (i.e., patients may be prescribed the wrong drug), addressing decreased drug efficacy caused by drug-drug interactions, and improving patient compliance with taking medications as prescribed. Another point he raised was about the current uncertainty about who should be leading the effort to implement pharmacogenomics in practice: geneticists, pharmacists, or pharmacologists? Finally, Dr. Newman also pointed out that current pharmacogenomics testing is “reactive”, where research is conducted only after a patient is shown to have an adverse drug reaction or no response. Ideally, we would like to reach a stage where pharmacogenomics testing is “pre-emptive" (i.e., all patients are genotyped ahead of time and this information is available to those prescribing drugs).
Final perspectives and considerations
This year’s ESHG conference created a wonderful environment for fostering knowledge exchange and collaboration and covered multiple topics of importance. To conclude, we leave you with some final considerations brought up in several presentations regarding the future in human genetics:
Existing barriers in human genetics research (e.g., funding/costs, regulation in different countries, general lack of awareness of molecular biology techniques, etc.) need to be overcome, and we should be encouraging multi-disciplinary research efforts and data sharing.
We must embrace population diversity in our sequencing initiatives and datasets to ensure equal health benefits from genomic advances. Despite repeated calls, limited progress has been made on this front and Eurocentric bias continues to grow (e.g., currently, most pharmacogenomics data have been generated for those of white, European ancestry).
Genetic counselling is highly beneficial as it can help patients adjust to their situations—with or without a diagnosis. Genetic counselling needs to be more equitable in both private and public healthcare settings.
The DNA Genotek team was thrilled to interact in-person with the human genetics research community at ESHG 2022 in Vienna, Austria. If you were not able to attend or missed us, keep an eye out for us at upcoming conferences!
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