Who benefits from whole genome sequencing in the NICU? Who suffers?

Annie and I recently published a letter to the editor of Pediatrics and Child Health about the ethical implications of using Complete Genome Hybridization (CGH) as the default test for possibly genetically determined disorders in pediatrics. CGH is a very high resolution way of examining the DNA of an individual, and finding abnormalities that do not hybridize to the standard DNA of the chip. Although much higher resolution than a standard high resolution karyotype there are several risks that come along with that increased resolution. Those risks are (as enumerated in our published letter):

  • CGH often reveals minor DNA anomalies that are of uncertain significance, leaving a child labelled with a DNA anomaly, but with no idea whether it is of medical importance.
  • CGH may reveal significant DNA anomalies that are not related to the condition being investigated; these unrelated DNA anomalies may have implications for the future health of the child.
  • Finding DNA anomalies in the infant will often lead to the parents being tested. This testing may reveal that they also carry the DNA anomaly, which may have implications for the parents’ future health or may impact their insurability.
  • Because CGH is often performed when the diagnosis is uncertain, it is impossible to counsel parents regarding potential implications of the hundreds of possible diagnoses that might follow, or the potential future health impacts.
  • CGH may reveal DNA anomalies that could affect (or will, in the future, be shown to affect) the health status of the infant including risks of cardiovascular disease or cancer risks.
  • CGH may reveal DNA anomalies that are associated with an increased risk of future mental health or behaviour problems, but with what is referred to as ‘reduced penetrance’, ie, they are not very specific. How can we (and do we currently) counsel parents that the CGH test we are performing might reveal that their child has an increased risk of future antisocial behaviour, bipolar disorder and schizophrenia,  (This is not theoretical, this has actually been demonstrated!) but that even if their child has the relevant microdeletion, the occurrence of these problems is not certain, and we cannot do anything to prevent them anyway?
  • CGH results provide a permanent record of DNA anomalies, and the test is performed on an infant who is unable to understand or consent.

Now that is for CGH, imagine the next step up in resolution, sequencing the entire genome.  Some of you may have seen press releases from Children’s Mercy Hospital in Kansas City about whole genome sequencing, available for newborn babies within 3 days. The hype from that center states things like ‘one third of babies in the NICU have genetic disorders’ and ‘physicians can make practical use of diagnostic results to tailor treatments to individual infants and children’

Well I must live on another planet. The large majority of babies in my unit are there for prematurity. Now unless you really want to hype your own research and stretch the meaning of the phrase ‘genetic disorders’ to include possible potential SNP’s in the mother that might in the future be shown to maybe increase the risk that she will deliver prematurely, then that is a downright lie. A lie that will disturb parents and helps no-one. The only people who will be helped by that are those making profits from the test, which costs “only” 13,500$. The entirely spurious comparison of the cost of the test to the cost of neonatal intensive care made during interviews by the authors is equally inane and self-serving.

It is very likely that there are genetic variants that increase the chances that you will develop BPD if you are born prematurely,  or variants that make you more susceptible to RoP or Group B Strep sepsis etc. etc. But that is entirely different to calling them genetic disorders. It is also entirely different from being able to tailor our treatment to the condition. Even in the case of what have previously considered genetic disorders, there are a minority that can be directly treated. The main advantage of a diagnostic label for many children is to be able to give a prognosis.

Lets imagine a case, a very realistic case that will happen one day soon. A baby in the NICU has a club foot. The genetics consultant isn’t sure if there is an underlying genetic cause (even though there was oligohydramnios and the neonatologist was quite happy that the cause was in utero constraint, but nevertheless the resident had filled out a consultation form for the geneticist before I could stop them) so they decide to sequence the genome of the baby. The lab reports 300 different unknown SNP’s none of which have previously been noted to be associated with club foot. They also find that the baby is heterozygous for a beta glucosidase mutation that increases risk of Parkinson’s disease to 16%.

Now what the hell do you do?

As far as we know there is nothing you can do about this. There is no prospect in the near future of being able to do anything about this. So do you keep quiet about it? Do you lie to the parents and say we didn’t find anything? Or do you leave the knowledge hanging over his head for the next 50 years?

If you actually read the article that this hype is based on you will probably be profoundly unimpressed. They actually report 4 babies in the NICU with possible genetic disorders. Three of the babies were critically ill and had active care discontinued, the 4th is having cardiac surgery. For the 3 babies that died 1 had a condition that could have been diagnosed from his clinical presentation, 1 they didn’t figure out, even with whole genome sequencing, one turned out to have an abnormality in a gene only reported once before as a cause of their problems. The baby with heart disease clearly had an autosomal recessive condition, and the authors may have discovered a new gene causing visceral heterotaxy.

So who benefitted from the whole genome sequencing?

None of those babies benefited.  3 of them had care withdrawn because of the severity of their clinical condition, the 4th still needed to have heart surgery.

We read in a tiny footnote to the article the following “J.F., S.H., P.S., Z.K., J.C.W., J.B., R.J.G., E.H.M., and K.P.H. are employees of Illumina Inc., which manufactures the HiSeq 2500 instrument.” The initials refer to 9 of the 23 authors of the article. (That’s right an article about 4 babies with 23 authors!) So Illumina Inc will benefit if they sell their machines.

Children’s Mercy Hospital will benefit if they get more referrals. (in the US medical “system” the more sick babies you get referred the more money you make, even at a wonderful non-profit organisation like the Mercy Hospital a lot is driven by money, because they have to stay open, so they have to keep working on their “market share”).

The authors benefit from having a publication in a high profile journal

Clinical scientific knowledge benefits from knowing a bit more about genes that can cause epilepsy and visceral heterotaxy.

But the babies? The families? There certainly is at least a risk that the babies and families might suffer, they might have findings that are of unknown significance, that cause only concern. They might have findings that are of known significance, but have nothing to do with the reason for doing the test. They might have findings that have profound implications for the future health or future life expectancy of the baby, and they will very often be untreatable.

I certainly wouldn’t have whole genome sequencing, nor accept it for my children. If there was a good research project, I would let them take my blood (or my mouth swab or whatever) but I don’t want to know the results thanks very much! A press release suggesting that this technique makes a difference in clinical management, that it is cost effective, and that it could be applied to 1 in 3 NICU patients serves no-one… except Illumina Inc.

About keithbarrington

I am a neonatologist and clinical researcher at Sainte Justine University Health Center in Montréal
This entry was posted in Neonatal Research and tagged , . Bookmark the permalink.

One Response to Who benefits from whole genome sequencing in the NICU? Who suffers?

  1. Fiona Miller says:

    Many thanks for your insightful critique. Too few are being aired at the moment.

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