Genome DNA testing in healthy people – what can you find?
Benefits of sequencing your genome
The clinical utility of DNA sequencing has been showcased frequently for patients with pre-existing conditions, whether that is some rare disease or cancer, in adults, children, and prenatally. The truth is that the entire world is moving towards the clinical adoption of DNA sequencing, and the question is only to what degree. We have looked previously at past data that showed the rate of incidental findings when sequencing a population. Typically DNA testing is done to diagnose a specific condition, and any additional health-related discoveries made are incidental to the original purpose of the test, hence its name. But much controversy has stirred up around the utility of sequencing healthy people to uncover medical information about them that otherwise might not be available to them or to their doctors.
The primary benefits of the medical genome sequencing test for presumed healthy individuals is that the test can achieve following:
• uncover their risk of disease development for hundreds of different conditions;
• learn about their drug response in order to help determine right medication dosing or potential toxicity of a given drug;
• discover any cancer predisposition;
• investigate their carrier status for reproductive purposes: what mutations do they have that if their partners also have, would run the risk of having a child with that disease.
The majority of potential consumers for genome sequencing in the world fall into the category of healthy people that could utilize this technology for such pre-emptive screening purposes. There is much excitement surrounding such use of this technology, and very high quality tests are already available on the market to satisfy the demands of this target group.
However, very little scientific data has come out to assess the utility of genome sequencing in healthy people. While thousands upon thousands of papers have been published on the use of DNA tests in helping to diagnose conditions in order to help manage existing health problems in the population, very little attention has been paid to healthy people sequencing their genomes, despite the fact that thousands of people have already done so.
In this article we will bring it close to home, and see what type of findings have been published thus far with regards to sequencing in healthy populations. This will help to answer the question: if you were to sequence yourself as a person currently free of any disease symptoms, what are your odds of uncovering something alarming?
Or how beneficial is genome sequencing to you?
Earliest attempts at DNA health testing
To answer that question, we will analyze the entirety of the published scientific information that I am aware of related to this topic, which is only four publications. Undoubtedly there is more, but not yet uncovered by me. The charge was lead in 2014 from Stanford University, and it included 12 people without the manifestation of inherited disease who had their genomes sequenced. Nine of them were sequenced again with a separate technology, so this study was more about measuring technical performance in these still early days of sequencing.
Overall, all of the participants received information on variants (scientific way of saying mutations), with potential disease-risk implications, ranging from 2 to 6 per person, including 1 to 5 mutations associated with adult onset diseases. However, most of these were accounted for by variants of unknown significance, and the data was not presented in terms of how many patients were impacted.
Also all of the participants were carriers of mutations of recessive inherited diseases, with a range of 8-18 variants per person. Again, most of these were variants of unknown significance, and because of how the data was presented, we cannot tell how many participants without variants of unknown significance were affected.
Eleven participants (92%), carried one or more genetic variants associated with changes in drug dosing or administration.
Of the 56 genes listed by the American College of Medical Genetics and Genomics (ACMG) as the genes of highest medical significance, and used as the minimum gold standard around the world as genes to be reported on if mutations are found (recently upgraded to 59 ACMG reportable genes), 5 participants carried 1 or more mutations cataloged in databases as disease causing, and 9 participants had mutations deemed to likely be disease causing. Again, we do not know how many total participants were affected.
But we do know that after the expert analysis, it was determined that only one person had a disease-risk variant in the ACMG reportable genes that was very likely pathogenic. It was a deletion (the segment of a DNA code missing), in the BRCA1 gene, resulting in an elevated risk of hereditary breast and ovarian cancer. It was in a woman who otherwise would have not met the family history referral criteria for genetic testing.
As a consequence of this important finding, the woman underwent the removal of her entire reproductive system (ovaries, fallopian tubes, and uterus), and was recommended for intensified imaging–based breast cancer screening. As for the other variants in the other participants, the medical experts decided to reclassify these to uncertain significance status. Thus in this small cohort study, 8% of participants had a pathogenic variant that was listed in the ACMG list of reportable genes and that required medical intervention.
This study highlights the problems of the early days of sequencing, where the databases used were problematic by listing too many unverified variants as potentially disease causing. These in part were due to the overzealousness of reporting attention-grabbing scientific findings of significance (a general problem of scientific reporting), which can make its way to databases whether the finding is verified or not. Since then, public databases have been developed that score DNA mutations based on an accumulated level of evidence, thus dramatically increasing the accuracy of the interpretation. Nevertheless, we are still not in the age of full automation for the clinical interpretation of the DNA code, and the best quality genome tests require manual oversight of all results before reporting them. This is an important differentiating factor between DNA tests currently available on the market and touted to unsuspecting doctors.
In this early version of the test, everyone received some results – for most, seemingly a warning of future possibilities, and one requiring serious medical intervention. A doctor’s review of the genomic results lead to 1–3 initial follow-up referrals and diagnostic tests per participant, with estimated costs generally less than $1000 per person. The study did not look at the further impact on medical management beyond these immediate measures, so we cannot know how these early warnings played out in the future of these participants health.
Exome versus genome for personalized healthcare
The next oldest study, from 2015, is a publication that comes from Israel (and all participants were Caucasians of Jewish origin). Unlike the other research presented, the genetic testing for health purposes, undergone in Israel was done by analyzing the exome instead of the full human genome.
The exome comprises under 2% of the entire human genome and encodes genes, the part of the DNA program that informs the cell how to produce all of the proteins that will do all the work in the cell. The remainder of the genome, more than 98%, is actually information of how these genes should be used, so regulatory information, or just junk. The human genome is very malleable to change, and to some degree is changed in every single individual that is born (so yes, you can always proclaim now without any hesitation that you are unique). But along the way, some DNA leftovers are present that might no longer serve any purpose. Some of our DNA is simply viruses, that have embedded themselves (and can be a contributing factor to producing that change in our genomes from person to person).
So why test the exome instead of the full genome? There are a few factors. First of all, the majority of diseases stem from mutations in our genes. We are only slowly discovering how the non-exome part of our genome also contributes to disease development, as now more and more people are having their entire genomes sequenced. At the time of that study, the cost of clinically decoding your exome was likely higher than the current cost of clinically decoding your entire genome. The above-mentioned Stanford study estimated that the cost for genome sequencing and interpretation at the time was $14 815 USD. In 2015, it was still pretty unheard of to invest such funds into a study of presumed healthy people.
Now with the cost of medical genome sequencing being much cheaper, you have the advantage of capturing the entire DNA information of high quality in one test, providing access for a doctor’s interpretation to augment a patient’s personal history for the duration of a patient’s life. No information loss also allows us to probe into how DNA outside of our genes can contribute to disease, including large alterations in the genome, where very large chunks of the genome are moved around, duplicated, or completely lost.
Nevertheless, this was still a unique study to look at healthy individuals.
How did they manage to justify this at a time when DNA sequencing was routinely examined for diagnostic capabilities in sick people? The authors commented that nearly 100% of the surveyed general public desire signiﬁcant clinical ﬁndings obtained from DNA testing, to be reported to them, echoed closely by more than 85% of surveyed medical geneticists wanting to report DNA health test results to patients.
What did they find? Of the 25 participants, 24% had significant variants that have led to clinical interventions. These included mutations in cancer predisposition genes, cardiac disease genes that are recommended by the ACMG to be reported, and genes impacting drug dosage or toxicity. Of those who had mutations related to diseases, all had personal or family history related to the uncovered genetic conditions.
Unfortunately, the way the data was presented was not very clear, but it appeared that 88% of the participants had mutations related to cancer or cardiac disease risk. No distinction was made to differentiate pathogenic status and carrier status among this listing, but 76% of the participants had cancer predisposition mutations, and 28% had cardiovascular disease mutations. That is a really high level of cancer predisposition risk in this group, although the Ashkenzi Jewish population is known to harbour high rates of cancer risk mutations. The results also showed that 84% had mutations affecting drug dosing or administration.
In the end, this study also showed really high rates of results of medical significance in the studied population.
The birth of a new era of health with genetic testing
The third oldest study is an American investigation published in 2017, known as the MedSeq Project. In this analysis of genome sequencing in healthy people, the test was unusual in that it tested for everything mentioned above, plus the study of risk factors affecting heart fitness based on an assessment of many mutations contributing together towards one particular heart-health problem. In total, 8 different heart conditions were looked at, with each condition represented by the collective effect of many mutations. These are referred to as common complex diseases, common because they are frequent, and complex because many factors contribute to their development, whether by many mutations, or by factors outside of our body, like choice of diet, how active we choose to be, how clean our surrounding environment is, our medications, or our stress level, to name a few. Some of these can be very far outside of our control, like how we were raised and the surrounding pollution.
This scientific examination of DNA testing for health included a rare clinical look into the utility of genetic predisposition for one of the most common killers in a global population. While the biological complexity of these diseases precludes the clinical use of such a test right now (while often readily advertised by commercial tests, so doctors beware), this area is expected to produce very valuable results in the future of medicine.
This particular paper made quite a stir in the media when it came out due to couple of findings: one pointing to the potentially serious benefit of the pre-emptive sequencing of human genomes, and one that was used as an argument against it.
Let us examine this paper in detail and the spanning controversies. This study was also special in that it was a randomized clinical trial, and the patients were randomly assigned to receive medical management based on standard family medical history, or family history complemented by a whole genome sequencing test (with 50 participants in each group).
The explosive outcome was that 22% of the participants who underwent DNA testing for health analysis received a previously unknown disease risk result. This essentially indicates that if you sequence yourself, you have a 1-in-5 chance of discovering a mutation related to a disease. Clearly you can see how this type of announcement would grab attention, and how this might promote DNA testing for health reasons.
To specify, this risk refers to the monogenic diseases, meaning those diseases that stem from a mutation affecting the proper function of a single gene. This is in contrast with the complex diseases mentioned above, as the link between the mutation and the disease is much easier to work out.
Of these, 7 participants had pathogenic or likely pathogenic variants, meaning they are associated with disease development. That is a whopping 14%! Only one instance was labeled as a risk factor for health problems, and 3 individuals had variants of unknown significance but with suspected pathogenic implications. Typically, risk factor mutations increase your likelihood of developing a disease, but are not necessarily the cause of the disease.
The second controversy was that only 4% of the participants showed evidence of the diseases predicted by the genome sequencing test. This sure was used as an argument against health DNA testing! But that is actually not fair, as this outcome was referring to 4% of the entire cohort of 50 people, meaning that it was 2 out of the 11 people who received a previously unknown disease risk result. That means of the people who did receive the relevant DNA test results, 18% exhibited the symptoms, making it a very different statistic.
On top of that, it has to be noted that this was based upon any patient follow-up for 6 months only. Thus, it cannot be ruled out that the other people identified with genetic conditions would not eventually express diseases symptoms. In addition, this included patients whose mutations were of unknown significance but were suspected of a pathogenic nature. Here, the unknown mutations might turn out to be benign after all in the future, and hence would never result in disease symptoms. Finally, it also included patients who did not have a doctor asses them for the expected problem in the 6 months of the monitoring period, as was seen with a case of a patient with a pituitary hormone deficiency, so maybe there were already uncovered symptoms present.
Moreover, the conditions in people that were genetically identified and correlated with existing symptoms have been trivialized in the media. They included difficulty with adaptation to low light, and occasional rashes due to skin sensitivity. Here it perhaps would appear that a patient’s only benefit is to obtain a confirmatory genetic diagnosis, but there could be additional benefits not immediately appreciated. First of all, having a clear diagnosis means patients no longer have to investigate the cause of their observed symptoms. Especially for skin rashes, there can be many potential reasons that a patient could worry about as to what is causing them. However, the diagnosed condition can also include mental disturbances or seizures, and this might be valuable information for a patient and the family to become aware of.
Another person was diagnosed with a very serious condition of Long QT syndrome which can lead to an irregular heartbeat and even result in sudden death. The patient did not show evidence of this disease, but might benefit from future screening in case the condition starts developing as Long QT syndrome can present at any stage of life. Again, this is an overlooked benefit.
Other benefits included all patients learning about having at least 1 carrier mutation (with up to 7 observed in one participant), and 96% of participants “received a pharmacogenomic result indicating atypical or nonstandard response to at least 1 medication.”
None of the studies analyzed the potential benefits of DNA health testing to the patients' family members, which adds to the clinical utility of the test.
Single DNA test in a lifetime
In addition, the above-mentioned study indicated that doctors who received the results recommended new clinical actions for 16% of the patients using only family history for medical management, but for 34% of patients with a genetic health test, primarily including recommendations to specialists for specific conditions and also electrocardiograms and some blood work. This translated to the average cost for the immediately recommended actions being at $41 (range from $0 to $1063), in the family history only group and $68 (range from $0 to $603), in the DNA testing for health risks group. During the 6 months of the study, the costs averaged $1142 (range from $0 to $10 704), in the family history only group and $1490 (range from $0 to $15 026), in the health genetic testing group.
There is the funny issue with the argument that sequencing healthy people for disease predispositions might increase healthcare costs. If you look at the above expenditures, it is obvious that some people require a massive financial investment to analyze and manage their health. We are talking about up around $15,000 even in such a small sample of 100 presumed healthy individuals. This shows you how expensive healthcare can be, and in that case, the cost of such a powerful tool as DNA testing for health issues, which in the case of a full genome test currently costs a few thousand dollars for a clinical test, is not much of an investment. Especially since if the full genome is sequenced, it is a single genetic test for health which is needed for a lifetime. As authors of one of the quoted publications put it: “whole genome sequencing captures the entire compendium of variation in 1 experiment”. Science speak – so beautiful and so weird at the same time! The point is that an obtained DNA sequence can always be reanalyzed in perpetuity as the need arises, or as medical knowledge expands.
To me personally, this is actually not the most striking revelation that was presented in the recent American study however. I found it much more exciting to read that 41% of the participants who had their genomes sequenced reported making a health behavior change after 6 months! Which really is all a doctor could wish for, with patients changing their lifestyles for the better, and the ultimate goal of sequencing: for you to pre-emptively improve your lifestyle, while being guided in the best direction. In comparison, 30% of patients with only a family history analysis changed their lifestyle, which is also a pretty good number. Those must have been some pretty persuasive physicians!
Canada gets on the map of genomic testing of healthy people
The most recent study of the effect of sequencing presumed healthy or “ostensibly healthy” participants (13% had history of cancer, 13% had cardiovascular disease, and 20% had neuropsychiatric disorders), came from Canada, published earlier this year. The project was run by Personal Genome Project Canada, which aims to develop a database of information linking genome information with health traits, and the potential effects of integrating DNA genetic health testing into the routine healthcare system.
Similar to the recent American study, 25% of the participants had variants with obvious health implications. That sounds pretty alarming if we were to start sequencing everyone and discover this many potential health problems! But let’s break this group down:
• 6 variants in 5 participants (or 9%), were pathogenic or likely pathogenic. Of these, 2 participants had a personal or family history indicative of health complications predicted by the DNA test results.
• 7 participants had risk factors for cancer, cardiovascular, or neurobehavioural conditions. For two of these no comments were presented on family or personal history, and 4 of the remaining 5 had history relevant to uncovered genetic problems.
• 4 variants in 3 participants were associated with cancer, cardiac, or neurodegenerative conditions but remained of uncertain significance because of discrepancies among databases. One person had a family history of cancer.
• Finally, in one participant a large structural chromosome aberration was uncovered with unknown significance, and another participant harboured a likely pathogenic mitochondrial variant. No medical history was available for these two folks.
• For those where medical history could be assessed (13 people), 7 either exhibited symptoms or had family history supporting the presence of the predicted condition. In total, 2 of these were people with symptoms related to predicted genetic disease, so 15% and similar to what was seen in the recent American study.
Also similar to the American study, 93% of the participants were carriers of autosomal recessive pathogenic variants (meaning a mutation of the same gene from each parent has to be inherited to result in disease; average of 2.77 variants/participant). All participants had variants associated with a risk for altered drug efficacy and/or adverse reactions (average of 3.9/participant). Of these, 23% participants had risk mutations for severe and potentially life-threatening adverse drug reactions.
Interestingly enough, only 1 pathogenic variant (in BRCA1), was uncovered that is listed by the ACMG guidelines as gene mutations to be reported. This corresponds to the 1.8% chance of pathogenic mutation incidental finding, in line with previous evidence.
Based on these preliminary results, the authors boldly concluded that “whole genome sequencing will likely become part of mainstream health care in the foreseeable future”. I wholeheartedly agree.
To recap, if you were to sequence your genome, the data suggests that you have about a 25% chance of uncovering a significant finding related to your health which could require a change to your medical management, whether that would be immediate treatment, screening, or altering drug prescriptions. Approximately only 15% of such individuals might have supporting evidence of symptoms. Then 2–5% might be diagnosed with a serious pathogenic condition (or even higher depending on your ethnic origin). And nearly everyone will be informed of the carrier status of disease mutations that might have important reproductive consequences, or obtaining information related to drug dosing or toxic response.
These are pretty good reasons to why one should think about getting a medical genome sequencing test. If that is your will, Merogenomics can help you gain access to such tests. While this article provides some taste of the type of results that might be uncovered, in the future article we will look at what are the most frequent health problems discovered as a result of DNA sequencing for medical conditions.
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