There has never been a better time to be a geneticist. Medical genetics emerged from basic science only a few decades ago, but it has evolved into an incredibly exciting specialty with a dizzying array of possibilities for improving healthcare. In this post, we explore the future of genetics, specifically pediatric genetics, through a conversation with two leading experts, Dr. Jerry Vockely and Dr. Stephen Kingsmore.

Geneticists are traditionally viewed as diagnosticians of last resort, whom patients approach after a long odyssey of appointments and tests. A pediatric genetic consult is a thorough undertaking, involving physical examinations that involve looking for phenotypic variations, creating pedigree charts, performing pedigree analysis, and ordering genetic and metabolic tests. While the basic elements of the consult have remained unchanged, genetic testing has evolved rapidly in the past couple of decades, altering the role of the geneticist in turn. During this conversation, Dr. Vockley speaks on the technological advancements that have proven to be game changers: the mass spectrometer and whole exome testing.

Genetic testing: the journey so far

Between twenty and ten years ago the mass spectrometer revolutionized testing, allowing geneticists to run tests for multiple variants at once rather than having to order one test at a time. This meant that many patients could receive a definitive diagnosis at a much earlier stage.

While there were incremental improvements in the following decade, the next big shift was the advent of whole exome sequencing in 2009. Now, instead of having to pick a single test or a panel of tests, geneticists could run a relatively inexpensive comprehensive whole exome test that could identify potential causal variants, even those not originally considered by the geneticist . With whole exome testing, the journey from the first evaluation to the diagnosis was compressed by an order of magnitude.

The future: From exome to whole genome

As revolutionary as exome testing is, it will not be long before it is replaced for good by whole genome sequencing.

“We are big believers in the power of a genome, and we’ve been doing it for six years,” says Dr. Kingsmore. “Other tests are transient, instituted initially because people were afraid of the data load and because genome testing was more costly. Neither reason applies anymore. Genomes are where the action is. It's the most complete test, replacing a battery of things we used to do.”

Whole genome testing and diagnosis are exciting because turnaround times for results are astoundingly short. Where it took a month to return a whole exome sequencing test result, results can now be returned within a day. This is made possible with the help of artificial intelligence and the introduction of handling capabilities for large data sets - discussed for decades, and now implemented in daily practice. AI helps analyze the genome in real time, and has redefined the standard of care in many pediatric subspecialties.

Dr. Kingsmore cites a case where a mere 13.5 hours elapsed between receiving a blood sample and the diagnosis of a rapidly progressive disorder, and 37 hours from symptom onset to prescribing the patient life-saving medication. He also tells the story of a boy who had an initial positive newborn screening test for SCID. Decoding his genome took only 92 hours. When it was discovered that he had Artemis SCID, a lethal condition, he was transferred to UCSF, where he received ex vivo gene therapy to replace his broken Artemis gene.

This kind of near-instant genome sequencing and rapid therapy is what geneticists strive to make available for every genetic disease. This is well within reach, and no longer in the realms of science fiction.

Whole genome sequencing as newborn screening

If whole genome testing is the future, are we ready to adopt it for newborn screening? Traditionally, newborn screening in the US includes a battery of tests, decided by a federal panel. As of now, this consists of about 36 primary diseases, and a dozen or two dozen secondary ones.

This is a far cry from the many thousand genetic diseases that we know exist. Whole genome sequencing could show us a comprehensive picture of an individual’s disease-causing variants.

But how much information is reasonable to know, and when?

Dr. Vockley says: “I find merit in the idea of screening for something that's going to impact the baby in their first year of life. If it's something that's going to be developing when they're 10, would you want to pick that up now?”

He suggests age-appropriate screening, with a staged unveiling of genomic data as time goes on, rather than overwhelming parents with too much information all at once.

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“We could do whole genome sequencing on all newborns, but choose to only pull out relevant newborn disorders and give a readout to the parents. With the EMR software in place, we should be able to go back, query it at periodic intervals, and consult with parents accordingly.”

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These staged consults can yield other rich benefits. While a person’s genome doesn’t change with time, geneticists’ understanding of variants does. Periodic revisits of genome data would help them communicate pertinent, updated information to patients. Additionally, as diseases progress new clinical features arise, and when human phenotypes change this prompts a search for different candidates in the genotype. The benefits of revisiting genomes periodically extend across a lifetime, beyond pediatrics, to cancer genetics, psychiatry, and essentially every other specialty.

Dr. Kingsmore says: “We need to shift our thinking though, so that we're not thinking about disorders, but variants. Genomes pick up variants and genetic therapies treat variants - they are agnostic to disorders. We’re going to be asking, what is the variant pool in your genome? Is there anything there that we need to target?”

This shift means that geneticists can treat diseases before they even manifest as symptoms, as soon as a variance of concern is discovered.

The benefits of whole genome sequencing are indisputable. Besides the fact that it has the power to improve innumerable lives, genome-driven care saves millions of dollars in hospital fees and therapies. In the long term, the cost of the initial genome testing becomes almost insignificant. It seems like an obvious solution to move to whole genome testing for newborns - but there’s a catch.

Traditional newborn screening is inexpensive and covered by insurers. But whole genome sequencing and whole exome sequencing are still classified as research, and are not considered medically necessary, so insurers in the US do not cover the cost. For genome sequencing to become standard practice, insurers need to be convinced that doing whole genome sequencing is beneficial for them and will save them millions of dollars.

To hasten this change, the pediatric genetics community will have to focus on studies showcasing the economic impact of whole genome sequencing. Some of these studies have already paid off, with Medicaid and Blue Cross Blue Shield working on incorporating rapid genome testing for infants in intensive care units. Some insurers will be leaders and some laggards, but soon, covering genome testing will become an insurers’ competitive advantage.

Prospects and challenges for geneticists

While a geneticists’ practice continues to be considered primarily diagnostic, this looks poised to change. Therapeutics is the direct descendant of diagnostics, and geneticists are quickly progressing into a therapeutic practice where they take a curative position.

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“We get to beat the surgeons for the first time because we can cure disease,” says Dr. Kingsmore. “We’re going to fix the genetics in our patients before the progression of their disorder.”

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“We hope that the regulatory paths to move therapies into patients continue to evolve at breakneck speed.” Dr. Vockley adds.

Genetics has reinvented itself every five years. There isn't another discipline where the timeline between basic science, clinical and translational research, and routine clinical practice is as rapid. Dr. Jerry Vockley says that his only frustration is that the genetics community is not able to get this message through to medical students, who still prefer traditional specialties. He muses, however, that genetics will probably become a flagship discipline in the next couple of decades.

The frenetic pace of change comes with a challenge - that of upskilling the healthcare workforce to keep up with advancements. It’s not just MDs who require education, it’s genetic counselors, nurses, and social workers. It’s also neonatologists, intensivists, and hospitalists, who haven’t received significant formal clinical genetics education in their residency programs.

To bridge this gap, Dr. Kingsmore suggests practical, case-based learning - for example, 20 minute educational video segments. Dr. Vockley adds that AI takes some of the onus off the individual to remember a multitude of facts. The work of the geneticist becomes higher order thinking that fills in the gaps and makes sense of the literature that the AI creates. This enables day-to-day learning in the context of a patient, which is what healthcare professionals do best.

Dr. Kingsmore also suggests relying on the immense value-add that professional societies such as ACMG and NHGC provide. He adds that the pandemic has pushed us to invest in learning virtually, and that the means and ways to upskill are much better defined now than ever before.

We are accelerating toward a future in which healthcare looks fundamentally different, thanks to the intervention of genetic tests and therapies.