Rapid whole-genome sequencing is making a difference for acutely ill newborns
By Andrew Carroll, PhD, and Stephen Kingsmore, MD, DSc
Solving the medical mysteries behind the disorders of children with rare or uncommon diseases can be a harrowing journey filled with futile tests and misdiagnoses. Now, with the advance of genomic medicine, rapid whole-genome sequencing (rWGS) is offering answers and the possibility of a healthier life for acutely ill newborns.
Nationwide, nearly 15% of newborns are admitted to a hospital neonatal or pediatric intensive care unit (Figure 1).1 While the majority are premature and simply need time to grow, genetic disorders are a leading cause of morbidity and mortality in such infants.2 One in 33 babies in the United States is born with a genetic disorder.1 Among those newborns, 35% die in their first year; another 30% do not live to their 5th birthday.
The Diagnostic Odyssey
Finding a diagnosis is often a race against time. A single traditional test may take up to 90 days to yield results. In addition, standard diagnostic methods can be invasive and painful. For parents, the diagnostic odyssey means unnecessary suffering while searching for answers.
But there is new hope for children with genetic diseases. Care and treatment of the most fragile infants and children is being improved through rapid precision medicine (RPM)—a strategy that is poised to revolutionize the delivery of healthcare. In stark contrast to traditional diagnostic tools, rWGS offers the potential to provide a diagnosis within days instead of weeks or months.3,4 Timely, precise diagnosis through rWGS enables the RPM program to provide early targeted intervention that reduces suffering, empowers families, cuts costs associated with misdiagnosis, and ultimately saves lives.5–7
This healthcare revolution is being facilitated in part by the development of secure, scalable, Cloud-based software platforms that can maintain privacy and control of massive databases storing genetic data and other personal medical information. By securely allowing crucial collaboration, such technology has helped thousands of researchers across a spectrum of healthcare specialties accelerate their genomic programs to improve efficiencies and obtain rapid results, enabling physicians to provide early intervention and dramatically improve the lives of the most vulnerable children.
Taking the Lead
Leading the way in advancing pediatric precision medicine is Rady Children’s Institute for Genomic Medicine. Embedded within Rady Children’s Hospital, San Diego, the institute has recruited a world-class team of experts with the singular vision of making genomic medicine fast, easy, and fully integrated into the standard of care for acutely ill children with undiagnosed disorders. Rady Children’s is combining rWGS with expert analysis and interpretation to speed the diagnosis and treatment of genetic disease.
Researchers at Rady Children’s are committed to improving the lives of the most fragile children hospitalized in neonatal and pediatric intensive care units. The institute has assembled the expertise, infrastructure, and resources needed to engineer its integrated RPM program. The program combines rWGS with expert bioinformatics, clinical interpretation, data analytics, and phenotyping to deliver precise molecular diagnoses and enable earlier, targeted medical management of critically ill newborns and pediatric patients.
The institute has been offering rWGS to patients since the summer of 2016, and has sequenced the genomes of more than 350 children and their family members.7–10 As of the end of February 2018, the diagnosis rate at Rady Children’s is 34%, with consequent change in medical management at 70%.7 This is a remarkable rate of change in care, especially when considering that the institute’s efforts are focused on rare diseases and often involve genomic variants that have never been seen before. In some cases, the subsequent adjustment in care has provided immediate, life-saving, targeted treatment for rare genetic disorders, and helped children avoid unneeded, high-risk surgeries.
Rady Children’s has forged a strategic partnership with DNAnexus, Mountain View, Calif, provider of a Cloud-based global network for sharing and managing genomic tools and data to accelerate precision medicine research and improve patient care (see “DNAnexus: A Global Network“).11 The institute is making use of the company’s rWGS pipeline within its secure and compliant environment. With its Cloud-based technology, DNAnexus is also enabling other healthcare providers to use the Rady Children’s rWGS portal to expand data logistics capacity and analytics capabilities in a collaborative, cost-effective environment.
When all of these elements are brought together, precision medicine is no longer merely an academic exercise. Instead, it’s becoming a reality, with the goal of making genomic medicine the standard of care around the world (Figure 2).
The Challenges of Clinical Genomic Sequencing
Researchers are continuing their work to increase the number of known genomic disease characterizations and to drive down the costs of genomic sequencing. As such efforts bear fruit, the use of whole-genome sequencing as a tool to decode medical mysteries in children looks increasingly to be a potential game-changer for future healthcare. Nevertheless, clinicians will need to navigate through a number of challenges if they are to adopt genomic sequencing in everyday practice for infants and children.
Competing Methods. Whole-genome sequencing offers several important advantages when compared to exome sequencing and targeted panel testing. To begin with, whole-genome sequencing is faster, more uniform, and less technologically complex than either exome sequencing or targeted panel testing. These characteristics make rapid scaling of whole-genome sequencing both easier and more affordable.
Whole-genome sequencing can produce a full characterization of an individual patient’s genome within 20 hours, and at costs that continue to be reduced. By contrast, if they are to be cost-effective, exome sequencing and targeted panel testing require patient specimens to be submitted in batches. But accruing batches of samples can take a long time, and is a poor option for acutely ill patients in need of urgent answers.
Finally, whole-genome sequencing captures richer datasets than either exome sequencing or targeted panel testing, offering greater utility today and potentially greater benefits for the future, as our understanding of the genome grows. Whole-genome sequencing is also more uniform and less complicated than other methods, in the sense that there is greater consensus about what whole-genome sequencing entails, while the regions captured for exome sequencing are less standardized (Figure 3).
Building Collaboration. Health research and development is becoming increasingly global in nature, shifting from a siloed approach to a collaborative, dynamic learning loop. With clinical research and drug discovery moving to the use of Cloud-enabled systems, there is greater opportunity for scientists, researchers, and physicians to collaborate freely, regardless of geographic location, and to realize economies of scale.
As we move toward this future, the advent of new technologies such as the DNAnexus platform will be critical to incorporating genomics into everyday healthcare practice. By allowing data to be authenticated, tracked, and monitored in a single secure and compliant system, the DNAnexus platform reduces the logistical difficulties associated with this kind of work, enabling collaborators to focus on their research to uncover new insights.
The DNAnexus platform offers features that are uniquely suited for leveraging data to reveal new and meaningful insights. Core DNAnexus services deliver a secure and compliant environment where users can access data, run analyses, and collaborate freely.
Genomic Literacy. But perhaps the biggest challenge to incorporating whole-genome sequencing into standard care is the fact that most healthcare professionals are unprepared to put genomic medicine into practice. The majority of physicians are not trained to interpret genetic results and adjust treatment accordingly. Such limitations naturally complicate the task of relaying to patients and their families an understanding of the benefits of genomic medicine.
In order to reduce the barriers to precision medicine, it will be critical to increase genomic literacy among healthcare professionals, so that they are comfortable and competent with this emerging technology. There is also a critical need to revise electronic medical records and update reimbursement criteria and processes.
The Big Picture
With the advent of whole-genome sequencing, the future of rare disease detection and diagnosis is changing quickly—and it is clear that this is just the beginning of many more advances to come.
Rady Children’s Institute for Genomic Medicine is leading the way in this field by combining research and medicine in a way that is transforming healthcare for acutely ill infants and children. Already, the institute has expanded its offering of rWGS services to improve the treatment of patients at Children’s Minnesota, Children’s Hospital of Orange County, and Nicklaus Children’s Hospital. The institute’s goal is to extend rWGS to children’s hospitals nationwide.12
Still, there are hurdles and challenges to overcome. One thing that has become apparent is that operating in a single location has become an obsolete approach. Today, researchers share data and collaborate globally using Cloud-based networks. Platforms such as DNAnexus are facilitating this change by providing flexible and scalable technologies to enhance analysis and enable a highly optimized, end-to-end, rapid whole-genome solution.
Given the complexity and scale of researchers’ efforts to advance children’s healthcare, it will be essential to break down barriers that currently inhibit collaboration—whether across departmental divisions or national borders. Institutional infrastructure requirements will need to respond to researchers’ demands for technologies that will support seamless communication and data integration.
Adopting such technologies will help clinicians advance toward the ultimate goal: to ensure that genome-powered precision medicine is available to every family with a child who needs it.
Andrew Carroll, PhD, is vice president for science at DNAnexus, and Stephen Kingsmore, MD, DSc, is president and CEO of Rady Children’s Institute for Genomic Medicine. For further information, contact CLP chief editor Steve Halasey via [email protected].
- March of Dimes Foundation Data Book for Policy Makers: Maternal, Infant, and Child Health in the United States 2016. Washington, DC: March of Dimes, 2016. Available at: www.marchofdimes.org/march-of-dimes-2016-databook.pdf. Accessed March 8, 2018.
- Xu J, Murphy SL, Kochanek KD, Arias E. Mortality in the United States, 2015. National Center for Health Statistics data brief no. 267 [online]. Atlanta: Centers for Disease Control and Prevention, 2016. Available at: www.cdc.gov/nchs/products/databriefs/db267.htm. Accessed March 8, 2018.
- Saunders CJ, Miller NA, Soden SE, et al. Rapid whole-genome sequencing for genetic disease diagnosis in neonatal intensive care units. Sci Transl Med. 2012;4(154):154ra135; doi: 10.1126/scitranslmed.3004041.
- Miller NA, Farrow EG, Gibson M, et al. A 26-hour system of highly sensitive whole genome sequencing for emergency management of genetic diseases. Genome Med. 2015;7:100; doi: 10.1186/s13073-015-0221-8.
- Willig LK, Petrikin JE, Smith LD, et al. Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings. Lancet Respir Med. 2015;3(5):377–387; doi: 10.1016/S2213-2600(15)00139-3.
- Petrikin JE, Cakici JA, Clark MM, et al. The NSIGHT1 randomized controlled trial: rapid whole-genome sequencing for accelerated etiologic diagnosis in critically ill infants. NPJ Genom Med. 2018;3:6; 10.1038/s41525-018-0045-8.
- Farnaes L, Hildreth A, Sweeney NM, et al. Rapid whole-genome sequencing decreases morbidity and healthcare utilization in inpatient infants. bioRxiv. Preprint posted January 26, 2018; doi: 10.1101/253534.
- Farnaes L, Nahas SA, Chowdhury S, et al. Rapid whole-genome sequencing identifies a novel GABRA1 variant associated with West syndrome. Cold Spring Harb Mol Case Stud. 2017;3(5):pii: a001776; doi: 10.1101/mcs.a001776.
- Hildreth A, Wigby K, Chowdhury S, et al. Rapid whole-genome sequencing identifies a novel homozygous NPC1 variant associated with Niemann-Pick type C1 disease in a 7-week-old male with cholestasis. Cold Spring Harb Mol Case Stud. 2017;3(5):pii: a001966; doi: 10.1101/mcs.a001966.
- Sanford E, Watkins K, Nahas S, et al. Rapid whole-genome sequencing identifies a novel AIRE variant associated with autoimmune polyendocrine syndrome type 1. Cold Spring Harb Mol Case Stud. Epub ahead of print, February 1, 2018; pii: mcs.a002485; doi: 10.1101/mcs.a002485.
- DNAnexus powers whole-genome analysis network at Rady Children’s Institute for Genomic Medicine [press release, online]. Mountain View, Calif: DNAnexus, 2017. Available at: www.businesswire.com/news/home/20170503005939/en/dnanexus-powers-genome-analysis-network-rady-children’s. Accessed March 8, 2018.
- Sanford Children’s Genomic Medicine Coalition [online]. San Diego: Rady Children’s Hospital, San Diego, 2018. Available at: www.rchsd.org/programs-services/rady-childrens-institute-for-genomic-medicine/sanford-childrens-consortium. Accessed March 8, 2018.