For all of the enthusiasts of preventative medicine (and I hope you are one), recently a great scientific article has come out that helps bring the concept one step closer to reality. And if you do think in terms of preventative medicine, then this post is for you! Starring genome sequencing based preventative medicine. And babies. So how can you not read on?!

Important tests results of genome sequencing of newborns have come in, and, as usual, without much fanfare. There are massive studies underway in the US right now that are checking into the idea of what societal health benefits can be derived by screening babies upon birth with the sequencing of their genomes. This is a very laborious undertaking, combining the research efforts of many clinical institutions, as well as many scientists and physicians, and is scrutinized throughout the process from every angle possible. It is desirable to find out how good such sequencing would be for babies to be healthier, how accurate the process could be, how dangerous, how costly, and what impact can be expected. It will require many years of examination to bring all of the necessary data required to guide future health policies and standards.

This publication was definitely an important step in that direction.

But this publication was exciting not only because it provided results on how the examinations are going; it also provided a list of nearly a thousand genes that the study examiners deemed to be of verified importance in childhood disease development. These were important enough to consider paying close attention to these genes.

This is huge news, because it provides a very important extension of genes that could be subject to close scrutiny when genomes are sequenced by any individual. It also extends the medical significance of DNA sequencing tests. There are important guidelines to follow for laboratories handling sequencing. These guidelines are based on the principle of protecting the ordering physician and the end user from inaccurate service. Providers of genetic tests, whether in public service or commercial, are expected to adhere to these guidelines to be as safe as possible. Dealing with medically significant tests puts more pressure on the company providing the service to deliver as accurate information as possible. Otherwise, it exposes the sequencing service provider to liability.

The more genes that are medically assessed as important for clinical care, the sooner we will see them removed from potentially inappropriate use in currently available tests. This is the tricky part with genome sequencing. The sequence code is static. Interpretation of that code can change with time, and does rapidly. It is potentially easy to provide misleading information or misuse the test. One anecdotal evidence recently provided by the San Diego Naval Medical Center showed that 39% of ordered genetic tests were not used correctly!

Thus, the more scientific evidence behind a sequencing test, the more likely only appropriate information will be delivered to the client. This is important if doctors are to be looking at genomic information to help a patient, which these days is totally expected of them. And it will be totally expected that patients will continue arriving with genetic test results, including commercially-obtained results. This is a lot of information all of a sudden for doctors to expect to understand!

How do these genes help? It allows one to narrow in on specific genes, providing a clearer picture of the potential medical applicability, as the doctor is likely to obtain a genetic diagnosis. It also brings into focus diseases that the patient could be counseled about if necessary. Resources can be put into place to help improve the quality of counseling.

With regards to the published genes, the list is based on a stringent evaluation of clinical data. The type of information provided is powerful. 70 genes alone are based on actionability, where detection could lead to important medical intervention. That is already more than the classic gold standard ACMG list of genes to be reported that recently has been expanded to 59. This list include genes where early diagnosis might prevent a devastating childhood outcome, or significantly improve the clinical outcome of adult-onset conditions.

It also included 884 genes with definitive or strong evidence to cause highly penetrant childhood disorder (for a grand total of 954 genes). Even though they are not officially actionable genes, they are still important and impressive categories. Consider these:

• Disease is present at birth and immediate diagnosis is obtained.
• Disease is present soon after birth and treatment opportunities exist.
• Diseases are present in early childhood and the benefits of early intervention might exist.

These studies are great in another respect, as they point to what the professional organizations in the US view as valuable from genome sequencing newborns. This highlights the potential benefits of genome sequencing in general if done on an individual basis, including some in adults. It included genes with strong evidence for childhood-onset highly penetrant disease, genes with moderate evidence and/or moderate penetrance pointing to childhood intervention against a devastating adult-onset condition, pharmacogenomics genes, and the carrier status for any genes with the above criteria.

So the medical criteria and the scope of benefits based on genetic information appear to be increasing.

Parents whose babies were involved in these studies also had an option for obtaining information on all other adult-onset conditions. Only pathogenic and likely pathogenic variants from these genes are available.

But why even consider sequencing of newborns in the first place? Because genetic disorders and congenital anomalies are the leading cause of death in the Neonatal Intensive Care Unit. I imagine that the era of everyday genomics will be ushered in not by the people trying to be proactive about their own health, but rather the ones being proactive about the health of their children.

Let me tell you bit more about the type of genome newborn screening work that is being done in the US, which was beautifully laid out in a recent article published on the topic.

These studies are lead by a consortium of institutions, collectively called Newborn Sequencing in Genomic Medicine and Public Health, which somehow materialized into the NSIGHT acronym. I can see why, as Insight Consortium sounds so much better than the Ensgimph Consortium (NSGMPH acronym if first letters are used). So who do you work for young fella? Oh you know, Ensgimph study group. Acronyms are usually fun in science, and all of them definitely try to be witty, with varying rates of success. NSIGHT is a total winner, despite the obvious cherry-picking of the acronym letters.

NSIGHT has been tasked with the following key research questions:

• Can genomic sequencing replicate or improve a typical newborn’s screening test results?
• Can sequencing replace the current newborn screening tests?
• What can be gained from genomic sequencing regarding conditions not currently screened for in newborns?
• What can be gained from genomic sequencing that will benefit the clinical care of newborns?

There are 4 members of the NSIGHT Consortium which independently study different research questions and populations. These are some big names being involved here!

Brigham and Women’s Hospital (BWH), and Boston Children’s Hospital (BCH), at the Harvard Medical School, as well as the Baylor College of Medicine, are all assessing the impact of providing genomic sequencing information to the parents and physicians of newborns. This project is very well marketed under a colloquial name of BabySeq, which indeed is pretty catchy. Told you scientists like to be witty!

The study is enrolling healthy and sick newborns, and, within each group, the results are randomly chosen to be either conventional newborn screening, or screening augmented by genomic sequencing. Parents and physicians are surveyed for potential attitudes, preferences, utility, health behaviors and intentions, decision satisfaction, and for psychosocial impact on the family. Sounds pretty cool!

Rady Children’s Institute for Genomic Medicine and Children’s Mercy Hospital are studying the use of rapid whole genome sequencing for the diagnosis of rare genetic diseases. The goals are amazing, achieving provisional diagnosis in a mere 26 hours, at an analytic sensitivity and specificity of variant detection to >99.5%, all while gaining FDA approval for a verbal report to a neonatologist if the death of a child is imminent and the genome sequencing based diagnosis could change that outcome. Very powerful stuff. Apart from investigating the diagnostic utility, cost effectiveness, and psychosocial implications of such genome sequencing, the application is also analyzed.

The University of California, San Francisco (UCSF) and its collaborators are studying the use of the dried blood spots obtained during a typical newborn screening for exome sequencing. Except the samples are those that have been previously collected in the past decade, and newborns were identified with metabolic disorders, immunodeficiency disorders, or false results obtained with current screening methods. The goal here is to see if sequencing could either help or replace such tests. Broader legal issues are also investigated related to such approaches.

And finally, the University of North Carolina at Chapel Hill is studying exome sequencing from saliva samples in either healthy children, infants, or those identified as affected through regular newborn screening methods. Parents can decide about the pursuit of exome sequencing with the aid of electronic decision tools, and also about what type of results they would want. So this particular study wants to investigate how parents decide to learn, along with the issues surrounding the returning of results, and what the consequences are of the decisions undertaken after the results disclosure.

No one can complain about the US not doing their part in investigating the clinical utility of genome sequencing for the benefit of population health monitoring and treatment care! These studies aim to follow medical outcomes of sequenced children for many years; 18 years, in fact, for each child. Without even knowing yet, these children are the ground-breaking group that will help answer many questions about the potential future of genome sequencing in newborns.

What the outcome of these studies will be, only time will tell. What the public opinion is of these tests has yet to be fully determined, especially given the unresolved implications for both insurability and privacy of data, concerns which are ranking very high on people’s minds. Indeed, the uptake of genomic testing during the BabySeq project has been observed at a paltry 7%, in part due to such concerns, and in part due to the logistics of the undertaking. And that’s despite access to free testing, free counselling, complete medical oversight, and as rigorous an oversight of privacy protection as possible.

Dr. Robert Green, one of the leaders of the project and its primary spokesperson, has mentioned that these statistics incorporate all rejections, including even a brief casual interaction that resulted in refusal. Like when you poke your head in the door, and before you finish taking your breath to start talking, you are immediately kicked out. Which might be a very normal reaction soon after the delivery. A woman who just gave birth to her baby may not be too interested in hearing for the first time,”hey, would you be interested in placing your child in an experimental program?”

I had a chance to participate in interviewing Dr. Green on the topic, which was one of my personal highlights because I am a huge fan of the type of investigations into population sequencing that he oversees. At the time, I was pretending to be all cool, not a single facial muscle betrayed the huge party and celebratory fireworks going on in my mind when I had a chance to interact with him.

He did mention if the denominator for measuring rejection was a denial after a thoroughly explained consent, the measured acceptance rate would be much higher, over 50%. So the devil is always in the details. Green noted “we are scrupulous about reporting the denominator because we are interested in a paradigm of what might happen in the future when you imagine the world where everyone has an opportunity to be sequenced.” All the while “without trying to promote an agenda that sequencing will help them. We do not try to disguise it as research and say wouldn’t you like to be part of the future where you can get all of this great information for your baby. I think if you framed it that way you would probably get a better uptake for obvious reasons.” Consequently, involvement of genetic counsellors upfront to go over the details resulted in a much higher uptake by parents, as some misconceptions or barriers could be dispelled. And probably the news was delivered at a more sensible time. :)

The misconceptions or lingering worries will persist for long time to come I am sure. Especially around the topic of privacy in genomic sequencing and our rights to control access to it, even if it is for medical purposes only. I think it is normal that people would be inclined to think they should have the final say in who and when anyone should be looking into their biological code. It doesn’t get more personal than that! A genome sequence is the blueprint to make a specific unique human being. These big projects are undertaken to first and foremost figure out the benefits and potential harm of newborn genome sequencing, and to become a tool for screening, like many others used in medicine to improve individual health.

I can’t wait for the outcome of these studies to all be completed! And along the way we are collecting very valuable information as mentioned here. At Merogenomics, we look for the benefits and limitations of the technology being used. We seek the proof of that what excites us, but for the same reasons, we want to know what could be at fault too. That is also how the technology keeps seeing such rapid improvements, as so many expert eyes are scrutinizing its effect from so many angles. If you are interested in genome sequencing, you have come to the right crowd! There is plenty to talk about. And that is always an important point, as these topics deserve to be talked about, a lot, and I can guarantee you it is always a fun discussion to have with people. So share, and spread the word! This post just provides some flavour of it.

This article has been produced by Merogenomics Inc. and edited by Kerri Bryant. Reproduction and reuse of any portion of this content requires Merogenomics Inc. permission and source acknowledgment. It is your responsibility to obtain additional permissions from the third party owners that might be cited by Merogenomics Inc. Merogenomics Inc. disclaims any responsibility for any use you make of content owned by third parties without their permission.

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