Personalized medicine, the tailoring of medical interventions to individuals based on their genetic makeup, is becoming more popular. The global precision medicine market was estimated at $78.85 billion in 2018 and is expected to grow to over $216.75 billion by 2028. A key element is the advent of new genomic sequencing technologies, which enable the rapid analysis of large amounts of genetic information simultaneously and are dramatically changing how genomics can be applied to clinical care. Next-generation sequencing has greatly sped up the process of sequencing DNA (taking only days to weeks to sequence an entire human genome) while also reducing the cost involved with ending the “diagnostic odyssey.” The key to unlocking many of our healthcare mysteries, especially for orphan diseases may be found through whole-genome sequencing (WGS), but it is contingent on changing the approach we take toward routine and critical healthcare moving forward.
Benefits for Clinicians
The application and use of various sequencing technologies have dramatically increased, generating large amounts of data that has helped scientists and doctors better understand variations in the human genome, and how they relate to human disease. This data also helps clinicians make more informed decisions about medical management and ultimately the recommended course of treatment for patients and/or enrollment in clinical trials.
Whole Genome Sequencing vs. Whole Exome Sequencing
WGS and whole exome sequencing (WES) are both increasingly being used in a variety of healthcare and research settings. Both methods rely on next-generation sequencing technologies that allow the rapid sequencing of large amounts of DNA. The difference between WGS and WES is that WGS investigates both coding and non-coding regions of the genome, while WES only analyzes the coding regions (exome). It is well known that certain DNA variations outside of the coding regions (exons) can also affect gene activity and protein production, and lead to genetic predispositions to a variety of conditions, such as metabolism, neuromuscular, and eye disorders. These variations outside of the coding region are things that would not be detected by WES.
The literature and research defining the full diagnostic yield of WGS are still evolving. However, given that it is estimated that approximately 15%1 of disease-causing mutations are found in non-coding regions, the clinical yield for WGS is expected to be significantly better than standard WES.
WGS can be used in a variety of situations for patients, including patients having:
- a genetically heterogeneous disease meaning that the disease could be caused by a large number of different genes
- a condition suggestive of a genetic disorder, but there is a long differential diagnosis list
- an unclear or atypical presentation of a genetic disorder
- previous genetic testing that did not yield a diagnosis, including exome sequencing
WGS is extremely useful in finding diagnoses for individuals with symptoms suggestive of genetic disease but can also be useful in apparently healthy individuals that are interested in learning more about potential future disease risks, information about carrier status, and/or information about responses to certain medications. Several COVID-19 initiatives are ongoing in which WGS is being used in large patient cohorts to investigate for genetic clues as to why some individuals have a severe form of the disease and others do not. As part of these initiatives to better understand some potential cause and effect between genetics and COVID-19, we already know that genetic testing can proactively identify a number of different genetic conditions which may lead to increased susceptibility and severe illness. Ongoing efforts from the Clinical Genome Resource Actionability Working Group have highlighted over 150 medically actionable genetic conditions that can be proactively screened for in apparently healthy individuals. This group has identified over 70 genetic conditions where knowing a person’s genetic predisposition could be relevant to making important clinical decisions when treating patients who have contracted COVID-19.
Challenges with Genomic Data Storage and Analysis
The implementation of WGS as a routine clinical testing service has created new challenges for diagnostic laboratories. This ranges from both the amount of data generated through WGS and the subsequent long-term storage of this data set to the increased complexity involved in interpreting this data and applying it to clinical care.
Although it has its challenges, the potential impact of big data derived from WGS is immense. This underscores the importance of building an appropriate network and infrastructure to support the massive amount of information produced. Many of the medical discoveries of the future will depend on the ability to process and analyze large genomic data sets. Luckily, the ability to store data in the cloud is becoming more commonplace. Laboratories will continue to leverage advances in cloud computing as a necessary means to securely store data that may need to be retrieved later for data mining purposes. The availability of cloud computing and storage also makes it easier to use the multitude of web-based tools that are used to both analyze the data at the time of testing and/or access it later for data mining projects. Many of these tools and applications are being developed in-house by diagnostic laboratories to ensure superior oversight and flexibility in dealing with the large data sets derived from a high-throughput clinical genomics laboratory.
Educating Physicians
As more studies continue to be published, physicians are starting to understand that the uniformity of the data from WGS is far, far superior than WES. However, there needs to be a concerted effort to provide more education to physicians about the benefits of genome sequencing and genetic testing in general. Given the potential benefits of understanding a person’s genomic make-up, there should be a continued focus on integrating genomic medicine into mainstream clinical medicine. Case-oriented education can be more useful than trying to give presentations around what WGS or WES is as it helps demonstrate the actual clinical application of the product. There are now numerous published studies showing the benefits of integrating WES and WGS in the diagnostic process, specifically with critically ill patients like in the NICU. Integrating genetic testing sooner in the diagnostic process is key to solving many diagnostic dilemmas sooner while providing relief to patient families and should be made a point of emphasis in education.
Making WGS Mainstream
The continued utilization and application of whole-genome sequencing will be essential as we continue to work to understand the genetic underpinnings of disease – both through current diagnoses and further research. WGS will continue to play a pivotal role in determining timely and appropriate tailoring of the patient’s medical management. It will also potentially open up new avenues for clinical trials, which in time may lead to new treatments for many rare diseases. However, this will also require policy challenges surrounding how to optimize patient engagement, ensuring data privacy, and distinguishing research from clinical uses. It will also be critical to determine the benefits of WGS through economic modeling which considers multiple diagnostic modalities to convince payors of the overall benefit and cost savings. The possibilities for WGS are almost endless and will provide individualized care for people across the globe.
Author Notes:
Dr. Hegde is a medical geneticist, a board-certified diplomat in clinical molecular genetics by the American Board of Medical Genetics, and a fellow of the American College of Medical Genetics and Genomics. Previously, she was the Executive Director of Emory Genetics Laboratory. She received a B.Sc. and M.Sc. from the University of Bombay and a Ph.D. from the University of Auckland. She completed post-doctoral studies at Baylor College of Medicine.
References:
1. Taylor, J et al. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders. Nat Genet. 2015 Jul;47(7):717-726, PMID 25985138.