Genetic Screening of Newborn Babies

Universal newborn screening with whole genome sequencing (WGS) is coming to the UK - at least on paper. There are conditions for which this would seem to clearly make sense, many for which it would be a disaster, and a vast area of grey in between. The government has ambitious plans to roll out WGS for all newborn infants by 2035, but the practical and ethical implications of this are not 10 years away.

Friends of mine are expecting their third baby, and they recently agreed to take part in a research study called Generation Study. This research involves performing genetic screening at birth for a selected set of 200 genetic conditions, and is being undertaken to better understand the implications of the UK government’s ambitious WGS plans.

We discussed their thought process behind consenting, and then they asked me, “Would you have entered your children into this study?”

I paused. Probably for longer than I should have.

Part of it is almost certainly my own philosophical biases about healthcare in childhood. But part of it is due to my apprehension about combining two topics that have great validity and simplicity at face value, but in reality are fraught with practical and ethical complexity.

Genetics

Genetics is of increasing importance within my own specialty (I am a combined paediatric immunology and infectious disease specialist), but it’s become clear it is far more complicated than we previously thought. Two siblings with identical genetic mutations can have vastly differing disease phenotypes - something I witness in my clinical practice. The idea then that we can simply identify any problem with any gene and immediately predict the outcome for the patient has been proven false. Finding variants of uncertain significance (VUS) or uncommon types of mutation make interpreting many genetic results very challenging.

Despite this, it has undoubtedly brought important progress. We have children with conditions that we have understood from the ground up; finding a genetic VUS has prompted more targeted functional testing of the immune pathways involved to clinch a diagnosis. These findings are not academic but have changed the targets of our treatment.

Screening

Despite its many issues in other settings, screening also undoubtedly has huge benefits in paediatrics. In the UK we currently screen for 10 conditions using the newborn blood spot test. One of the best examples is Cystic Fibrosis, the most common life-limiting genetic condition in the UK. We now have drugs which may completely re-establish normal life expectancy for children with CF (CFTR modulators), and the earlier treatment can be started, the better the long-term outcomes.

The criteria for adding to the UK screening list are so strict that no additional conditions were added between 2015 and 2022. This makes it even more challenging to contemplate universal WGS in the next decade.

Why not combine the two?

Testing children with a specific disease phenotype for a targeted set of genes that could be implicated is uncontroversial. Performing genetics tests on a well child prior to symptom onset is a different story.

There are two ends of the spectrum. Take Spinal Muscular Atrophy as a positive example. Because the condition has a clean genotype with bilateral loss of the SMN1 gene, testing will generate few false positives. The intervention window is also extremely narrow, with the new and relatively effective therapies needing to be commenced within the first few months of life to make a big difference to outcomes.

Then there are diagnoses that almost everyone would agree we should not screen for. Huntington’s disease is completely incurable, and the child’s family being aware from birth of this eventually and unavoidably lethal diagnosis is agreed by most to be unethical.

Between these two ends of the spectrum is where things get murky. There are inborn errors of immunity included within the Generation Study which result in immune dysregulation and autoinflammation, which do not usually present with symptoms until later in childhood. Symptoms are then managed responsively, with monitoring for pre-symptomatic inflammation in the interval periods. Should we be screening for these disorders? What do we do with a newborn baby who has not yet developed any symptoms of their disorder, and who would otherwise be living a normal life? Do we monitor them prior to symptom onset? Is there a role for pre-emptive anti-inflammatory treatment? These are not rhetorical but actual clinical questions; questions we have had to ask as children diagnosed as part of this study have come to our service.

Whilst being aware of my particular philosophical stance, I sometimes can’t help but feel that we have stolen something from the infant’s childhood by unearthing their diagnosis before its manifestation. Years spent as a family without doctors’ visits, without health anxiety, and without labels. The sense of normality. These things are precious, and for children with genetic conditions, will not be recovered once lost. Where we can be certain that taking this from a family earlier in life will improve the child’s health and longevity, it seems a worthwhile cost to bear. In some instances, things are not so clear.

What is the future?

Wherever you live, genetic screening at birth seems inevitable once costs have fallen sufficiently, and they are falling rapidly. The Human Genome Project cost more than $2.5 billion by its completion over 20 years ago - we are now approaching sequencing an entire genome for $100.

There are many important questions that need to be answered about the particulars of this testing. Should we be sequencing every child’s entire genome, and if so, what do we do with the data after screening? What rights should the child have to this once they are an adult? Should we test only for specific conditions, and if so, which ones?

I feel that equally stringent criteria should be applied to these conditions as are currently applied to the UK’s existing screening program. There are significant harms in causing confusion and uncertainty with findings that are non-definitive. The aims when designing the program should be to maximise test specificity and to focus only on conditions where we have clear evidence that early diagnosis improves longevity and quality of life. Where this is unknown, screening should only be implemented in a limited research setting.

So, would I have enrolled my children in the study if I’d had the chance? I honestly still don’t know. Would the risks of getting a diagnosis that is uncertain, or unclear if truly actionable, outweigh the potential benefits of getting a life-saving diagnosis in the first weeks of life?

I guess that’s what they call equipoise.

Dr Alasdair Munro is a paediatric specialist in both infectious diseases and immunology, and a clinical trialist working in the UK. He runs vaccine and antibiotic trials. He is on Substack at The Munro Report.

Photo Credit: Filip Mroz