The Future of Commercial Genetic Testing

Abstract

Purpose of review:

There are thousands of different clinical genetic tests currently available. Genetic testing and its applications continue to change rapidly for multiple reasons. These reasons include technological advances, accruing evidence about the impact and effects of testing, and many complex financial and regulatory factors.

Recent findings:

This paper considers a number of key issues and axes related to the current and future state of clinical genetic testing, including targeted versus broad testing, simple/Mendelian versus polygenic and multifactorial testing models, genetic testing for individuals with high suspicion of genetic conditions versus ascertainment through population screening, the rise of artificial intelligence in multiple aspects of the genetic testing process, and how developments like rapid genetic testing and the growing availability of new therapies for genetic conditions may affect the field.

Summary:

Genetic testing is expanding and evolving, including into new clinical applications. Developments in the field of genetics will likely result in genetic testing becoming increasingly in the purview of a very broad range of clinicians, including general pediatricians as well as pediatric subspecialists.

Introduction

The genetic and genomic testing landscape continues to evolve rapidly. Multiple related factors affect which genetic tests become available clinically. These include: improvements in laboratory-based and computational methods; expanding knowledge about the causes and manifestations of genetic diseases; emerging molecular and other therapies; data regarding the effects of genetic testing in many different situations; complicated financial and byzantine regulatory factors. This is all set against a backdrop in which genetic testing companies are opening, closing, merging, and otherwise transforming at a dizzying rate.(1) While the field’s trajectory holds great promise to benefit many individuals, it also results in a complicated and ever-shifting landscape that can be difficult to leverage, especially for clinicians who are not genetic specialists.(2)

It should also be noted that genetic testing is at least theoretically available in virtually every clinical setting imaginable, from prenatal to postmortem settings, and for healthy individuals as well as those affected by mild or severe conditions affecting any organ system. In this review, rather than covering every clinical scenario, we will focus on genetic testing that is applicable to the field of pediatrics. We will also mainly discuss clinically indicated testing, versus “recreational” genetics that might be done for the sake of curiosity or for less evidence-based reasons, though the lines can be blurry. There can also be blurring between research-based and clinical testing, as patients may, for example, have clinical genetic testing and simultaneously be enrolled in research studies that involve genetic analyses. Finally, we will not shy away from controversial topics, though the opinions in this paper should be viewed as the author’s views and predictions rather than the universally accepted beliefs.

A very brief history of clinical genetic testing

Genetic testing has been available for many years, but the types and scale of genetic assays have grown enormously in the last several decades. The initial completion of the human genome project (HGP) approximately twenty years ago (3) ushered in a new era of clinical genetics. Among other contributions, the HGP enabled a tsunami of discovery of the causes of genetic disorders. This directly led to a sea change in the ability to provide specific genetic answers for people suspected to have genetic conditions.(4)

Since the HGP, subsequent technological advances like next-generation sequencing and rapidly improving bioinformatic methods also contributed to dramatic developments in genetic testing, as described below.(5) Recently, a third wave of sequencing technologies, again coupled with diligent computational work, have enabled researchers to “fill in” the missing areas of the genome that were not previously able to be interrogated or analyzed.(6) These same methods may also allow new types of genetic testing, such as to more rapidly identify clinically important variants or detect certain types of genetic changes easily missed with other types of testing.(7) Finally, an increased understanding of the fact that disorders that are classically considered to be genetic conditions can be caused, detected, or tracked by assessment of RNA, methylation, and via other biomarkers, has led to growing efforts to incorporate testing beyond DNA-based analyses.(8, 9)

Targeted versus broad approaches

In a very general sense, genetic testing might be divided into targeted versus broad, “hypothesis free” approaches. A targeted test asks whether a person has a specific condition that is suspected based on medical history and physical examination. For example, a clinician may be concerned that a macrosomic neonate with a very large tongue and a pronounced umbilical hernia may have Beckwith-Wiedemann syndrome, so they will send targeted testing for that condition.(10) On the other hand, that same clinician may later evaluate a child with unexplained global, severe developmental delay. There are many genetic causes of developmental delay, including chromosomal anomalies and pathogenic variants (“mutations”) in thousands of different genes. The clinician may decide that the most efficient and cost-effective approach would be broad testing, such as exome or genome sequencing, which can examine the individual genes as well as detect many types of structural changes affecting the chromosomes.(5, 11, 12)

To be clear, hypothesis-free genetic testing is not new – older approaches include routine karyotypes, and then microarrays, both of which can detect certain types of cytogenomic anomalies. These older approaches did not allow for the routine detection of individual, base-level genetic changes, and the diagnostic yield was therefore lower in most clinical scenarios. Current sequencing-based methods, like exomes and genome sequencing, can detect cytogenomic anomalies as well as assess many (or the vast majority of) known genes.(13) Thus, due to technological improvements, genetic testing is shifting more towards these hypothesis-free approaches, where the primary questions have changed from: “what specific disorder does the patient most likely have?” to “is there enough suspicion of a genetic condition to warrant broad testing?” and “are there any specific signs of conditions that would necessitate a more targeted test instead of starting with broad testing?”

Overall, these ongoing technological advances will continue to lead to a democratization of genetic testing. Rather than being the sole purview of clinical geneticists, it is likely that pediatric clinicians from many specialties will increasingly order genetic testing applicable to their area of practice, though they may still need physician geneticist or genetic counselor guidance for especially complex or esoteric situations. A similar situation has arisen in oncology, where many medical and surgical oncologists routinely order and manage genetic testing, and triage results to geneticists as needed.(14) The democratization of genetic testing has also been driven by the unfortunate dearth of physician geneticists.(15)

Simple and Mendelian versus polygenic and multifactorial testing

Currently, genetic testing focuses on relatively simple (though biologically complex!) causes of disease. For example, genetic testing may reveal an extra copy of chromosome 21 in an infant with clinical signs of Down syndrome, or that a recent adoptee with failure to thrive has pathogenic variants in the gene related to cystic fibrosis. Some of these follow Mendelian inheritance patterns, while others do not, but all intrinsically involve a single genetic cause, whether that cause relates to an extra copy of an entire chromosome or a change in one “letter” of the person’s genome. (To complicate matters somewhat, a small but significant percent of people undergoing genomic sequencing are found to have multiple genetic causes that explain their clinical presentation. For example, a child with signs of Down syndrome as well as failure-to-thrive might be found to have both trisomy 21 as well as pathogenic variants in the gene related to cystic fibrosis.(16)

As opposed to the above types of conditions, there is considerable interest in using genetic testing for many common, multifactorial conditions, such as most cases of asthma, diabetes mellitus, or short stature. The overall idea is that a person with one of these conditions may have many genetic variants, each of small effect, that combine, along with non-genetic factors such as environmental exposures, to influence the risk of disease. Genetic testing using polygenic risk scores (PRS) can look at many genetic variants simultaneously to assess whether a person may be at increased or decreased risk of the condition.(17) While there is strong evidence for the potential of PRS at the population level, use at the individual patient level remains largely in the research sphere at this point, and may continue to remain so for some time.

Population screening

Most people are referred to geneticists due to suspicion of a genetic condition. In this situation, genetic testing may reveal an explanation. On the other hand, individuals may be identified as having a genetic condition through a general screening program. One such example is newborn screening.

In many countries, newborn screening programs have long-standing and highly successful programs to identify and therefore better treat infants with genetic and other congenital conditions. Alongside other assays, targeted genetic testing has long been part of these screening programs, but newer technologies have raised the possibility of using genomic sequencing as part of newborn screening. For the last decade, a number of studies have explored these possibilities.(18–21) Based on data garnered from this research, initial clinical pilots are now being launched for multiple population groups, including infants and children.(22) While many issues around population genomic screening have been discussed, the relatively high price of sequencing has largely restricted these activities to a research-only or theoretical space. As the cost of sequencing drops, these types of sequencing-based screening programs are likely to increase, and their scope (the number of conditions they involve and the number of individuals screened) are likely to.(23, 24)

With these shifts, pediatricians will encounter more patients with genetic diagnoses that have been made either presymptomatically or in individuals with occult or complex medical conditions not previously suspected to be genetic in origin. There is already precedent from “secondary findings” efforts in current clinical genomic sequencing. For example, a child may undergo clinical exome or genome sequencing because she has multiple congenital anomalies. In addition to trying to identify the cause of her congenital anomalies, it has been recommended that a set of genes be analyzed that have general healthcare implications, such as related to the risk of cancer or cardiovascular disease.(25) A few percent of individuals undergoing such sequencing are found to have reportable secondary findings, and having management guidelines and resources (26) for these scenarios will be important as more individuals with these conditions are identified.

The need for speed

One of the most impactful developments over the last decade has involved the advent of rapid genomic testing.(27) These approaches have been most (but not exclusively) studied in neonatal intensive care settings, where they have been shown to be cost-effective and improve care, including for diagnosed individuals and those without explanatory results. Using rapid sequencing can help inform decision making, identify optimal management strategies, and avoid unnecessary interventions.(28–31) Current speed records – which are sure to be continue to be broken – involve the ability to provide answers via genome sequencing in well under a day, and multiple commercial labs can provide results in under a week.(32, 33)

In addition to the NICU and PICU, rapid genomic testing will likely expand into other clinical areas and contexts, which will lead to improved care for patients and families. It would not be hyperbole to describe the evidence of benefit for rapid sequencing to be overwhelming. In the United States, surmounting the next major barrier – obtaining wide insurance coverage - will allow these benefits to be unlocked for the good of a larger swathe of society than just those fortunate enough to have strong insurance coverage and to be born in an academic medical center. However, as with other emerging technologies, there is a risk of exacerbating disparities, both in the United States and worldwide.

The rise of AI

Artificial intelligence (AI) affects just about every part of medical care as well as society more generally. The field of genetics has, in many ways served as a harbinger of the future in relation to AI (34, 35) While many clinicians may not be aware when they order a genetic test, AI-based tools and approaches are already a mainstay in commercial laboratories, enabling more efficient and accurate identification of genetic variants and clinical interpretation of genetic tests.(36–38)

In the clinic, many geneticists as well as other clinicians have adopted use of apps that use a type of AI called deep learning to analyze photographs of patients in order to generate a differential diagnosis and therefore guide genetic testing.(39) For example, a clinician may encounter a patient with distinctive facial findings that raise the suspicion of a genetic condition, but may not recognize the specific syndrome. These apps can help inform the differential diagnosis (and can incorporate other medical information, such as the presence of certain clinical features) and testing approach.

Studies have shown that these types of tools may be effective in many other contexts related to clinical genetics, such as assessing birthmarks, analyzing ophthalmologic imaging, and evaluating EEGs or radiologic studies, to name just a few.(34, 40, 41) In the future, there will be likely tools that can assess more and more data types, including photographic and radiologic images, results of laboratory-based testing, clinical notes, and other medical records.(42) These tools will be used to help select the optimal genetic tests for just about any clinical encounter, and can be used to bolster the discussion between clinicians and patients and families.

As with broad sequencing approaches, these tools may further democratize clinical genetics and genetic testing by putting knowledge at the fingertips of many clinicians. In many ways, genetic testing is ideally situated for help via AI, since the field involves so many rare and esoteric conditions that any one clinician (even a geneticist) cannot possibly be expert in every disorder they will encounter.(43–45). However, robust implementation studies are needed to carefully examine the efficacy of these tools.

In theory, the use of these AI-based methods, including large-language models, may also be able to free clinicians from the tyranny of the Electronic Health Record, other documentation requirements, and prior authorization and other hurdles that insurance companies have erected as a barrier to genetic testing access.(46, 47) However, this is a double-edged sword, as AI tools may enable business-driven health care administrators to squeeze clinicians for increased productivity at the expense of clinician wellbeing and the ability to talk to patients and families for reasonable amounts of time about healthcare decisions.(48)

Moving towards therapeutics

For many years, clinical genetics has been a diagnostically focused field. The primary role of the geneticist has been to try to figure out the underlying cause of a person’s medical condition. However, once answers were reached – or if it were felt that no further answers were likely – the geneticist’s role would recede. An important exception involves biochemical geneticists, who care for patients with inborn errors of metabolism, many of which require careful and expert management of diet and medical interventions, including in both acute and chronic settings.

There has been notable growth in the ability to identify therapies for many genetic conditions, including via gene therapy, gene editing, and other molecular methods. Because of this, genetic testing will become more directly important to medical management, as precise molecular diagnosis will often be required for treatment eligibility. Geneticists will have the opportunity to become more involved in therapeutic as well as diagnostic efforts, and to work with other medical teams to help manage the patient.(49)

Conclusion

Genetic testing continues to undergo rapid change. In the future, genetic testing is likely to become broader, faster, and used in a wider variety of healthcare situations. Pediatricians and other clinicians will likely increasingly encounter individuals who have specific genetic diagnoses and will need to become increasingly fluent in appropriately triaging and managing these situations.

Key points.

• Genetic testing is and will remain a rapidly evolving field.

• Genetic testing will be driven by faster and more comprehensive testing, as well as growing availability of therapeutics for people with genetic conditions.

• The process of genetic testing will be driven by tools that will enable more practitioners and patients to select, order, and understand genetic tests.

• The use of genetic testing will continue to increase in all areas of medicine, including by practitioners who are not geneticists or subspecialists.