Newborn baby being held
Credit: Genomics England

Nearly 20 years ago, The Human Genome Project announced the sequencing of about 90% of the human genome.1 That success spurred a crucial question: When will this information improve healthcare? Just this year, scientists completed the sequencing of the entire human genome.2 Still, clinical sequencing—using genetic variants to identify or treat diseases—faces crucial obstacles to becoming widely available.

In 2019, leading scientists from several major national genomics programs reported: “Five years ago, genomic sequencing was restricted to the research environment.”3 As they added, this technique “is increasingly used in clinical practice.”

In fact, the use of next-generation sequencing (NGS) can now be found in clinical use around the world. According to Kathryn Phillips, PhD, professor of health economics and health services research at the University of California, San Francisco, and her colleagues, clinical applications of NGS exist in “both high-income countries with robust genomic programes such as the USA and the U.K., and growing availability in countries with upper-middle-income economies.”4 Nonetheless, the clinical use of NGS still needs fine tuning. In another study, Phillips and a team of colleagues pointed out that “not all NGS tests with demonstrated clinical utility are fully implemented to achieve population health benefit, and conversely, tests without known clinical utility may still be implemented.”5

Still, some studies already reveal the value of applying clinical sequencing in healthcare. One team of scientists in the United States studied the use of whole-genome sequencing (WGS) to test 354 acutely ill infants. The team showed that the “introduction of WGS was associated with a significant increase in focused clinical management compared with usual care. Access to first-line WGS may reduce health care disparities by enabling diagnostic equity.”6 In addition, scientists in the U.K.-based 100,000 Genomes Project sequenced 71,880 rare-disease patients and their immediate relatives to learn more about the genomic basis of a range of rare diseases. From this work, the scientists noted: “Of the genetic diagnoses that we made, 25% had immediate ramifications for clinical decision making for the patients or their relatives.”7 These studies provide just a few of many examples of the benefits of clinical sequencing, and many more surely lie ahead.

The available technology for clinical sequencing offers a broad spectrum of applications in healthcare, but implementation remains a challenge. Current programs in some countries, however, provide models that could be applied more broadly.

Excellence in England

“The U.K. has been a world leader in both the development of applications in clinical sequencing and the implementation of those,” says Matt Brown, chief scientific officer at Genomics England. For example, patients with rare diseases or cancer receive WGS or a test with a specific panel of genes. The choice depends on the best tool for a specific disease. “These tests are funded through the government and freely available to patients on the National Health Service,” Brown says. “So, it’s an extremely well-developed, well-funded system that’s really cutting edge.”

Matthew Brown
Matthew Brown, MD
chief scientific officer
Genomics England

Part of the wide availability of clinical sequencing arises from the country’s healthcare system. “We have a national health system so we don’t have the challenges of access that occur in other countries,” Brown says.

In the future, England plans to use clinical sequencing even more widely. “There’s also genomics in common diseases,” Brown says. “England has a huge program called Our Future Health looking at the utility of polygenic risk scores as a way of predicting the likelihood of developing or having common diseases.” Over the next five years, Our Future Health plans to study five million people to explore applications of clinical sequencing in a range of common diseases.

Genomics England also hopes to apply clinical sequencing in people as soon as possible. Through its Newborn Genomes Programme, as many as 200,000 newborns will be sequenced.

According to Genomics England, these sequences from newborns will be “analyzed for a set of actionable genetic conditions which may affect their health in early years. This aims to ensure timely diagnosis, access to treatment pathways, and enable better outcomes and quality of life for babies and their families.”8

Sequencing in Scandinavia

Clinical sequencing already has a long history in Scandinavia. In 2012, for example, Nature reported: “Norway is set to become the first country to incorporate genomesequencing into its national health-care system.”9 Plus, this country established its Norwegian Sequencing Centre in 2009.

All Nordic countries are actively utilizing genome-wide sequencing in healthcare. Clinical sequencing is available and widely used in all university hospitals in Finland. “Two of the Finnish hospitals are doing sequencing locally, and the rest of them are either utilizing services provided by these hospitals or commercial vendors,” says Janna Saarela, MD, PhD, research director at the Institute for Molecular Medicine Finland (FIMM). Like England, most of the clinical sequencing in Nordic countries applies to rare inherited diseases and cancer.

In addition to the available access of clinical sequencing in Finland, the use is broad as well. “Some of the clinics are more active in using it, but at least all the medical genetics units are well aware of the opportunities and are actively using it for particular rare diseases,” Saarela says. “Similarly, I think all the cancer units are well aware of the opportunity and are using it as well for diagnosing and treating patients.”

Part of the application of clinical sequencing can depend on a country’s past. “There’s a long tradition of analyzing and studying rare inherited diseases from decades ago in Finland,” Saarela explains. “So there has been a natural evolution of including that in the clinical services.

Sequencing projects underway

Projects to enhance the use of clinical sequencing are underway in many countries. Some significant work to expand access to clinical sequencing comes from unexpected places, like Estonia. Home to about 1.3 million people in Northern Europe, this country is not known for strong healthcare. Estonia spends less than half of the European Union average per person on healthcare and has above average incidences of cancer.10 Nonetheless, this country is hard at work at collecting sequences. The Estonia Biobank is archiving sequences, and as a recent report noted: “The Estonian government is also investing in the realization of personalized medicine at the national level, with an initial focus on pharmacogenomics and application of genetic testing for common complex disorders.”11

Some countries rely on collaborations to collect more sequencing data. In 2019, for example, SingHealth Duke-NUS Genomic Medicine Centre opened in Singapore, and this facility is developing a registry of genetic disorders.

A network composed of clinicians to consumers makes up Australian Genomics, which works on many aspects of clinical sequencing, including the safe use of genetic information in healthcare. In August, this group announced support for the Australian Undiagnosed Diseases Network to study genomic data in hopes of finding markers for rare genetic conditions that lack diagnostic tools.

Some governments also develop plans to turn sequencing into better healthcare. One example is the France Genomic Medicine Plan 2025. According to the plan’s description: “The aim of this plan is to integrate very high-throughput genomic sequencing (STHD) into the patient’s care pathway and thus improve [their] care as well as current knowledge concerning certain pathologies.”12

To truly get the most out of clinical sequencing, though, even more experts must work together. That kind of thinking underlies the Global Alliance for Genomics & Health (GA4GH), which is an international nonprofit alliance focusing on making better medicine from genomic research. Composed of more than 600 organizations—from ones focused on patient advocacy and information technology to research and healthcare—GA4GH develops standards for sharing clinical-sequencing data. Such sharing will accelerate the healthcare knowledge that can be gleaned from strings of nucleotides.

North American challenges

Although Phillips and her colleagues described the U.S. clinical-sequencing program as robust, the lack of national healthcare in the United States creates inequities in access to clinical sequencing. In 2021, for example, Daniel Sheinson, PhD, a principal data scientist at Genentech, and his colleagues studied the impact of the Centers for Medicare & Medicaid Services’ national coverage determination, which was intended to expand access to NGS testing in patients with solid tumors. Nonetheless, Sheinson and his colleagues reported: “Testing rates in the African American and Hispanic/Latino groups were lower than those of the White group.”13

Resolving such disparities will depend on motivated efforts, and some groups are already working on expanding access to clinical sequencing across North America. For example, the Medical Genome Initiative, which consists of healthcare and research organizations in the United States and Canada, hopes to lead the way to more access to WGS in diagnosing genetic diseases. As a start, this group published suggested best practices, which noted that “members of this initiative strongly believe that clinical WGS is an appropriate first-tier test for patients with rare genetic disorders, and at minimum is ready to replace chromosomal microarray analysis and whole-exome sequencing.”14

Obstacles to expansion

At first glance, expanding clinical sequencing might seem to depend on acquiring equipment, like NGS platforms. Not so, says Brown. “There’s a lot of service development that needs to be done, which goes from consenting, sample handling, the logistics of the front end, and getting clinical characteristics of the patients properly documented, so that that can be brought together with the DNA sequencing to ultimately provide an answer at the other end,” he says. “And then there’s the analytic pipelines, which are also quite complex, and setting those up to enable that for a national scale program is quite a challenge.”

In addition, the sequencing information must be presented to physicians in a usable format. The application of clinical sequencing “requires the knowledge of the genes but also kind of their connections and usability in clinical practice,” Saarela says.

In some areas, such as common diseases, knowing what to do with a sequence remains difficult, especially in diagnostics. “There are ongoing translational research efforts testing whether risk scores, formed by hundreds of sequence variants each slightly increasing the risk of developing a disease, are useful in clinical practice,” Saarela says.

Given the range of challenges, countries intent on making more use of clinical sequencing must think more broadly. “It’s not just setting up a DNA lab,” Brown says. “It’s setting up the whole system that is challenging.”

Perhaps even more challenging, key social issues must be resolved. For example, biochemist and computational biologist Yan Asmann, PhD, of the Mayo Clinic in Jacksonville, FL, and her colleagues examined sequences in The Cancer Genome Atlas for germline and tumor exomes from ancestrally African and European patients for seven cancers. From this study, the scientists concluded: “Overall and positional lower sequencing depths of ancestrally African exomes in The Cancer Genome Atlas led to underdetection and lower quality of variants, highlighting the need to consider epidemiological factors for future genomics studies.”15

Alexander Charney
Alexander Charney, MD, PhD
project leader and associate professor of psychiatry and genetics and genomic sciences, Icahn School of Medicine, Mount Sinai

Some projects underway plan to address such inequities in genomic databases. A collaboration between the Mount Sinai Health System, the Icahn School of Medicine at Mount Sinai, and the Regeneron Genetics Center (RGC) is driving a human genome sequencing research project called the Mount Sinai Million Health Discoveries Program. “The Program aims to enroll one million Mount Sinai patients over a five-year period, making it one of the most ambitious projects of its kind and the largest RGC-supported sequencing effort to date,” says Alexander Charney, MD, PhD, project leader and associate professor of psychiatry and genetics and genomic sciences at the Icahn School of Medicine at Mount Sinai.

This project, which began enrollment in August, promises a gigantic dataset from a diverse patient population. The sequencing information will be combined with “advanced electronic health records systems, all supported by a digital health platform developed by Vibrent Health, which will provide a robust privacy-preserving platform for e-consenting, data collection, and engagement for clinical research,” Charney says. “The data generated from the program are expected to be more representative of the entire human population compared to earlier such studies, which have focused primarily on white people.” Plus, the “team anticipates that roughly 10% will be children under 18, and this population is not well represented in other types of genomic research,” Charney says.

The BioMe BioBank lab where patient blood samples are processed.BioMe is expanding into the Mount Sinai Million Health Discoveries Program. Icahn School of Medicine at Mount Sinai

Sequencing all around

In addition to the global expansion of clinical sequencing, one day it could be standard testing. “I think we’ll get to a point where everyone is sequenced if, let’s say, our genome sequencing comes down to a cost of $100 or something like that, which I think there’s a reasonable chance that it will in the next five years,” Brown says. “The analysis is then going to be a challenge in how you feed that back into the healthcare system and make it accessible in a way that clinicians who are not specialists in genetics can then use it.” That won’t be easy. As Brown sees it: “That will require a lot of development, but I don’t think that’s insurmountable.”

Some other applications of clinical sequencing might come even sooner. One could be pharmacogenomics, which reveals how a person’s genome impacts the response to a drug. Here, a person’s genome could be incorporated in an electronic health record. This information could be used to prescribe the right drug and dosage, as well as indicating the likelihood of side effects.

In the future, the most valuable benefits of clinical sequencing could come from combining it with other forms of technology. “No one test on its own is going to be the perfect microscope,” Brown says. “So we’re looking at ways of combining sequencing with imaging data, such as digital histopathology or MRI or CT scanning data, to come up with better ways of finding genetics-informed personalized medicine.”

Overall, Brown sees powerful uses of clinical sequencing ahead. As he says, “I think this is a major tool that’s going to enable us to change the practice of medicine from being one where largely we react and treat people once they have developed disease to being able to do something where we’re actually identifying people at high risk and preventing disease.” Such early diagnoses and prevention would completely change the health of people around the world.



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Mike May, is a freelance writer and editor with more than 30 years of experience. He earned an MS in biological engineering from the University of Connecticut and a PhD in neurobiology and behavior from Cornell University. He worked as an associate editor at American Scientist, and he is the author of more than 1,000 articles for clients that include GEN, Nature, Science, Scientific American and many others. In addition, he served as the editorial director of many publications, including several Nature Outlooks and Scientific American Worldview.

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