rWGS as way to the promise of precision medicine

Rapid whole genome sequencing (rWGS), the comprehensive method to determine the complete genome sequence of an organism within two days, is a useful tool to promptly examine human genetic material.

Over the last ten years, increases in next-generation sequencing technologies together with bioinformatic tools and pipelines have resulted in decreased sequencing and analysis costs and increased processing time. In general, it became more affordable for clinics to utilize precision medicine to develop more precise diagnostics, therapeutics, and prevention measures [1].

Newborn screening by WGS

Currently, rWGS’s advantages over cheaper genetic analyses such as diagnostic tests and rapid whole exome sequencing (rWES) techniques are still the subject of debate.

rWGS promises to be the elective approach for infants with diseases of unknown etiology in neonatal intensive care units (NICUs). By their nature, neonates are very vulnerable. Their diagnostic workup is challenging and disease progression occurs faster than in adults.

A randomized study on newborn screening published last year indicates that by performing rWGS, 15% of newborns’ outcomes are enhanced when compared to the palliative treatment they would undergo in absence of such analysis [2].

In 2018, California became the first U. S. state to offer rWGS for critically ill newborns diagnosing 71 primary genetic diseases. 35 of them are genetic conditions that occur in less than one in one million births. Doctors identified the exact cause of such diseases in an average of three days, rather than the four to six weeks with standard genetic testing, leading to changes in clinical management. The right medicines were prescribed sooner and difficult decisions to discontinue futile care could be taken [3].

As an emblematic example, the condition of a two-month old baby diagnosed for mitral valve regurgitation (a heart disorder in which the mitral valve on the left side of the heart does not close properly,) was decreasing despite the pharmacological treatment prescribed. Sequencing by rWGS identified that the clinical condition was caused by a genetic cardiomyopathy. This diagnosis directed the physicians towards a heart transplant and the baby was put on a transplant list immediately.

Without a diagnosis, he probably would have been switched to an alternative and more intense approach to prevent further complications [3].

The positive impact on healthcare

Adopting rWGS in NICUs resulted in substantial reductions in healthcare spending. While the genetic test itself is more expensive than other practices, healthcare costs decreased by elimination of unnecessary procedures and by reduction of the hospitalization time. In this case applying less invasive medical approaches decreased patient suffering and increased recovery time.  

rWGS can provide life-saving information for clinicians and family even when it is learned that a condition is not associated with a genetic disorder. 

A baby girl born with severe anatomic and functional heart abnormalities requiring heart surgery was diagnosed with hyperthermia after genomic investigation. This is a rare but life-threatening condition brought on by general anesthesia. When ignored by anesthesiologists, mortality during surgical procedure can be greater than 70%.

Further investigations pointed out the genetic change was inherited from her mother, who was then made aware that she had to take the same precautions [3].

This story illustrates the advantage, in terms of prevention, of having your entire genome sequenced.

It is reported that children who undergo WGS continue to accrue benefits over their life, in health outcomes and cost-effectiveness of medical therapies [4]. 

Downsides and Initiatives

At this point, one may wonder why rWGS isn’t a clinical routine practice yet. The technique has downsides which represent a matter of contention among medical ethics committees [5]. Expressly, some literature gives examples where sequencing would lead to overdiagnosis and overtreatment [6,7]. 

Generally speaking, clinical pictures require interpretation with a multi-factorial framework. 

Acknowledging this complexity requires the collection of vast amounts of genomic data to refine medical predictions while also obtaining as much detailed clinical information on the patient as possible.

Evaluating large datasets can lead to the discovery of new mutation patterns through an increased understanding of the biological process. These newly understood mutation patterns can then be associated with specific genetic disorders [8]. 

There are several ongoing initiatives aiming to decrease the barrier in place for widespread adoption of rWGS in clinical practice [3,9] and for use by national health systems worldwide.

The quality of diagnoses and the quantity of studies, projects and documented cases of successful rWGS application in infants and children are increasing daily. Only time will tell if this approach is the best path towards a precision medicine revolution versus a “ one-to-many” treatment approach for all ages.

Written by Anna Aldinio-Colbachini

[1] “Realizing precision medicine with whole-genome sequencing,” BioTechniques. The International Journal of Life Science Methods, 2021.

[2] D. P. Dimmock et al., “An RCT of Rapid Genomic Sequencing among Seriously Ill Infants Results in High Clinical Utility, Changes in Management, and Low Perceived Harm,” The American Journal of Human Genetics, vol. 107, no. 5, Nov. 2020, doi: 10.1016/j.ajhg.2020.10.003.

[3] A. Philippidis, “Saving Baby Nathan: California Medicaid’s pilot program Project Baby Bear delivers better outcomes at lower cost via rapid wholegenome sequencing of critically ill newborns,” Clinical OMICs, vol. 7, no. 5, Sep. 2020, doi: 10.1089/clinomi.07.05.16.

[4] D. Schofield, L. Rynehart, R. Shresthra, S. M. White, and Z. Stark, “Long-term economic impacts of exome sequencing for suspected monogenic disorders: diagnosis, management, and reproductive outcomes,” Genetics in Medicine, vol. 21, no. 11, Nov. 2019, doi: 10.1038/s41436-019-0534-x.

[5] T. Aitman, “Debate – Genome Screening: A Pandora’s Box,” 2017.

[6] R. M. Doyle et al., “Discordant bioinformatic predictions of antimicrobial resistance from whole-genome sequencing data of bacterial isolates: an inter-laboratory study,” Microbial Genomics, vol. 6, no. 2, Feb. 2020, doi: 10.1099/mgen.0.000335.

[7] B. J. Wilson, F. A. Miller, and F. Rousseau, “Controversy and debate on clinical genomics sequencing—paper 1: genomics is not exceptional: rigorous evaluations are necessary for clinical applications of genomic sequencing,” Journal of Clinical Epidemiology, vol. 92, Dec. 2017, doi: 10.1016/j.jclinepi.2017.08.018.

[8] “Precision Medicine at UCSF,” the University of California, 2021.

[9] C. R. Marshall et al., “The Medical Genome Initiative: moving whole-genome sequencing for rare disease diagnosis to the clinic,” Genome Medicine, vol. 12, no. 1, Dec. 2020, doi: 10.1186/s13073-020-00748-z.