Four years ago, within just one month of being born, Brynn Schutle nearly died twice due to lethal bleeding, both without a clear diagnosis. Today, she lives as a healthy four-year-old, receiving her treatment from the Cincinnati Children’s Hospital to help manage her rare genetic disorder, Factor XII deficiency [1].
This was possible due to whole genome sequencing. Whole genome sequencing (WGS) is a procedure that records the order of nucleotides (adenine, thymine, guanine, and cytosine) in an individual’s DNA [2]. By analyzing the sequence of nucleotides, WGS can detect and predict abnormalities in the DNA, potential genetic mutations, or increased risk of certain health conditions on a wide scale [3]. The prospect of a broad genetic test able to detect multiple variations in the DNA at once has intrigued both the research and clinical world and coincidently, early clinical testing is ongoing. However, it is pertinent to acknowledge the significant hesitation whole genome sequencing has received, leading to minimal implementation, despite it being nearly five decades since its first creation, more than a decade since genomic screening itself was implemented on a wider scale (especially for newborns), and a decade since whole genome sequencing was made theoretically possible in clinical practice [4].
Perhaps the best word to describe the reaction to the current sentiments towards WGS is “counterintuitive”. Counterintuitive to leave such effective methods on the forgotten, dark edge of the table. Counterintuitive to a field of constant innovation and novel implementation. Counterintuitive when considering the many, many people like Brynn who could benefit from WGS.
However, as this article will later show by illustrating the three main issues that are blocking WGS, simply a procedure’s effectiveness, unfortunately, does not make it easier to implement. In fact, the reverse tends to be true. Often, some of the most effective procedures have some of the most significant impediments and issues.
The first pitfall is probably familiar. Cost. For any medical procedure that intends to be widely used, it must first and foremost be affordable. Unfortunately, there are two groups that need the procedure to be affordable: the consumers and the healthcare providers. The consumer side seems obvious. Fundamentally, the consumers must be in a position to be able to afford such a procedure in order to translate to clinical practice. Historically, this was simply unfeasible. As early as 2015, the cost of one WGS was over $10,000. The cost of a WGS in 2005, a decade before? $10,000,000 [5]. In this light, the fact that WGS has been around for decades is quite misleading when questioning its implementation. Despite this, there exists another, more abstract, factor that one must consider that could increase the cost substantially. Physician interpretation. Dr. Lantos conveyed this perfectly, stating, “the availability of WGS might result in a large increase in testing by cautious physicians'' [6]. And one can hardly blame them. After all, the patient should be most aware of any possible genetic variation that could impact their lifestyle. However, this does not abate the inevitable increase in cost and appointments that follows every slight genomic risk, every bit of uncertainty, and every false positive. To many Americans, this is not feasible. Another aspect of cost is from the viewpoint of the providers, but with respect to the fundamental idea of scientific awareness. The sheer infrastructure to educate the entire population so they can all make informed decisions regarding consent and WGS is a Sisyphean task, especially in terms of money [7].
The second major roadblock to WGS implementation is privacy and consent. Expectedly, many would likely view that consent is absolutely required for any form of WGS that may reveal a diagnosis that is unwanted or even leak its way into a biorepository’s data [6]. To this, I agree. However, many from that vast majority would also agree then that informed consent is required. To this, I also agree. But in order for citizens to make informed consent decisions, there must first be an infrastructure to inform and educate the process of WGS. This is bad news because in order to create such necessary infrastructure, the money and logistics needed can serve as a tremendous roadblock. There is also a significant concern that patients might not want WGS at all after learning what it accomplishes and where the data could end up. For example, from an informed consent position, only 7% of parents agreed to have a WGS for their newborn [8]. But why would so many parents decline? Well, although privacy concerns are definitely a large factor, part of the answer is found in psychology. Many view the potential release of detrimental genetic variation as harming and distressing, and with a distinct lack of effective pre-symptomatic care and potentially years before adequate care is distributed to “screen-positive” patients, the sentiment of being in medical limbo is unsettling [9]. Both the necessary infrastructure to even facilitate informed consent and providing informed consent entirely both serve as significant impediments to WGS.
Finally, the third major issue with WGS is..........effectiveness? Yes, effectiveness. WGS is considered effective due to its ability to identify any seemingly detrimental genetic variation. WGS is considered ineffective due to its ability to identify any seemingly detrimental genetic variation. WGS is a procedure that tends to have a high volume of “noise”, which are false positives that ultimately are either incredibly insignificant in the patient or do not result in any symptoms. This was shown in a study with twins, where out of the 32 variants detected to be related to diseases, only one was relevant [6]. This issue is prevalent in research use as well, with a high volume of essentially useless information clouding the incredibly useful genomic observations [7]. Another noteworthy example is the private, commercial use of WGS, where high false positive rates run rampant [10]. Even with the monumental task of cost and consent figured out, ultimately, WGS itself may not be suitable in its current condition to be utilized efficiently today.
But where does that leave us with whole genome sequencing? In the most optimistic way possible, the best answer to that question is that we are in a better place than we were yesterday. Every day, we continue to develop new, novel solutions to fully implement this groundbreaking methodology into clinical practice and to bring this powerful diagnostic tool to patients, physicians, and researchers alike. For example, according to some accounts, recently, we have reduced the cost of an individual WGS to less than $400 in the United States, and online, if you take the time to search private procedures, we can find it for even less [11]. This trend is also taking place around the world. In Hong Kong, a start-up team is attempting to administer WGS for a price of less than $650 [12]. Additionally, the National Human Genome Research Institute (NHGRI) continues to develop new algorithms to expunge false positives in WGS [6].
Is whole genome sequencing a flawless procedure? No, far from it, and issues regarding cost, privacy, and data analysis are likely not disappearing anytime soon. But with enough time, and as developments in bioinformatics, cost, and public awareness foster, whole genome sequencing is definitely a blueprint that will undergo translation.
1. Ungar, Laura. “A Broad Genetic Test Saved One Newborn’s Life. Research Suggests It Could Help Millions of Others.” AP News, AP News, 28 Aug. 2023, apnews.com/article/genetic-testing-babies-newborns-whole-genome-cc27689e7f9deb88c9b0753d9cd0ba4b.
2. “Deoxyribonucleic Acid (DNA) Fact Sheet.” National Human Genome Research Institute, National Institute of Health, 24 Aug. 2020, www.genome.gov/about-genomics/fact-sheets/Deoxyribonucleic-Acid-Fact-Sheet.
3. “Whole Genome Sequencing.” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 15 Aug. 2022, www.cdc.gov/pulsenet/pathogens/wgs.html.
4. Marra, Marco. “Whole Genome Sequencing.” Encyclopædia Britannica, Encyclopædia Britannica, inc., 28 Aug. 2023, www.britannica.com/science/whole-genome-sequencing.
5. Wetterstrand, Kris A. “The Cost of Sequencing a Human Genome.” National Human Genome Research Institute, National Insititute of Health, 1 Nov. 2021, www.genome.gov/about- genomics/fact-sheets/Sequencing-Human-Genome-cost.
6. Lantos, John D. “Ethical and Psychosocial Issues in Whole Genome Sequencing (WGS) for Newborns.” Pediatrics, vol. 143, no. Supplement_1, 2019, https://doi.org/10.1542/peds.2018-1099b.
7. Botkin, Jeffrey R., and Erin Rothwell. “Whole Genome Sequencing and Newborn Screening.” Current Genetic Medicine Reports, vol. 4, no. 1, 1 Feb. 2016, pp. 1–6, https://doi.org/10.1007/s40142-016-0084-3.
8. Kaiser, Jocelyn. “Surprisingly Few New Parents Enlist in Study to Have Baby’s Genome Sequenced.” Science, American Association for the Advancement of Science, 19 Oct. 2016, www.science.org/content/article/surprisingly-few-new-parents-enlist-study-have-baby-s-genome- sequenced.
9. Flinter, Frances. “Whole Genome Sequencing in Newborns: Benefits and Risks.” The Nuffield Council on Bioethics, The Nuffield Council on Bioethics, 16 Feb. 2023, www.nuffieldbioethics.org/blog/whole-genome-sequencing-in-newborns-benefits-and-risks.
10. Tandy-Connor, Stephany, et al. “False-positive results released by direct-to-consumer genetic tests highlight the importance of clinical confirmation testing for appropriate patient care.” Genetics in Medicine, vol. 20, no. 12, 30 Apr. 2018, pp. 1515–1521, https://doi.org/10.1038/gim.2018.38.
11. Colby, Brandon. “Whole Genome Sequencing Cost [Updated 2022].” Sequencing.Com, Sequencing, 2023, sequencing.com/education-center/whole-genome-sequencing/whole-genome- sequencing-cost.
12. Shen, Xinmei. “Hong Kong Start-up Lowers Cost of Early Autism Detection Using Whole Genome Sequencing.” South China Morning Post, South China Morning Post, 31 Aug. 2023, www.scmp.com/tech/tech-trends/article/3232844/hong-kong-start-aims-lower-cost-early-autism-detection-using-whole-genome-sequencing.