As soon as he is born, a drop of blood is taken from your baby to screen for a dozen diseases for which treatment will prevent serious complications. Tomorrow, complete sequencing of its genome could detect more than 1000 genetic diseases for which we can act. Is such a development in neonatal screening desirable? Beyond the medical issue, having the genome of all newborns (and therefore ultimately of all citizens) raises numerous scientific, economic and ethical debates.
What if tomorrow, new parents left the maternity ward with all the genetic information of their child? The prospect is not as far-fetched as it seems, because many projects have already been launched in several countries. A tremendous hope for thousands of children or a worrying dive into Welcome to Gattaca?
Neonatal screening: genetic sequencing would make it possible to change scale
Neonatal screening (NND) already makes it possible to prevent or limit the occurrence of complications of diseases detected at birth. To date, it only concerns a small number of diseases (between ten and sixty depending on the country) for which there are preventive therapeutic means.
In Europe, it concerns 13 diseases (7 were added in 2023)1: phenylketonuria, congenital hypothyroidism, congenital adrenal hyperplasia, cystic fibrosis, MCAD (Medium-Chain-Acyl-CoA-Dehydrogenase deficiency) and, in certain populations, sickle cell disease followed by homocysturia, leucinosis, tyrosinemia type 1, glutaric aciduria type 1, isovaleric aciduria, long-chain hydroxyacyl COA dehydrogenase deficiency and uptake deficiency carnitine. The extension to severe combined immunodeficiencies (SCID) and that relating to sickle cell anemia for all newborns in mainland Europe, recommended by the HAS in 2022, are under study1.
For all of these pathologies, the DNN is based on a biochemical analysis. By moving to genome sequencing, this would make it possible to search for several hundred rare diseases.
Many projects already launched around the world
For the moment, there is no neonatal screening program using genomic sequencing in Europe and none is included in the Europe Genomics 2025 Plan. Conversely, projects are multiplying in other countries in England, in the United States, Australia…
- In the United Kingdom, the Newborn Genomes Program is evaluating the feasibility, benefits, and also the risks of whole genome sequencing. Included in the wider Genomics England plan, it is to analyze 100,000 genomes to look for a number of rare genetic diseases, between 200 and 400, which affect newborns and for which early intervention is beneficial. It is expected to begin in 2024;
- In New York, subject to parental consent, genome sequencing of newborns aims to detect 250 genetic diseases of pediatric concern. The first results of this program called GUARDIAN are expected soon;
- The “BabySeq” program brings together several centers in Boston, New York, Birmingham, Detroit and Philadelphia. It began with a study of newborns with intrauterine growth restriction and healthy newborns. It revealed an unexpected 11% rate of dominant mutations. Its second phase should involve 500 newborns, half of whom will benefit from genomic sequencing, the other half constituting the placebo group. The objective is to evaluate the medical, psychological and economic impact of screening by whole genome sequencing compared to conventional screening;
- In North Carolina, 25,000 newborns have already participated in a genetic DNN project called “Early check program” focusing on several genetic diseases (infantile spinal muscular atrophy, fragile X syndrome, Duchêne muscular dystrophy). The next stage will offer expanded screening for several hundred diseases, including type 1 diabetes;
- In San Diego, a whole-genome neonatal sequencing program “Begin NGS” aims to detect 400 rare genetic diseases;
- Three programs are also in development in Australia (“NewbornsInSA” in Adelaide, “Baby screen” in Victoria and “Melbourne genomes” in Melbourne);
- In Europe, projects are underway in Belgium (“Babydetect” in Liège which aims to detect 120 diseases), in Italy (“Screen4Care” in Ferrara) and in Europe, only the Dijon team has a project on a few dozen genomes to study the feasibility and medico-economic benefit of neonatal screening by genomic sequencing (“PeriGEN MED” in Dijon). The project is currently at the writing stage.
An international consortium bringing together all neonatal screening projects using genetics, called ICoNS, was set up in 2022 to identify current programs, harmonize studies and share data.
From a medical point of view, the benefits of such sequencing would make it possible to implement therapeutic measures preventing or limiting the development of a serious illness, to avoid a delay and very often diagnostic wandering, to avoid disabilities… Nevertheless, such a perspective raises a certain number of technical, ethical and economic questions2.
A significant investment in machines and training
How to implement genetic sequencing across the country? Can the sequencing of tumors (to give the right targeted therapy) implemented by the various Cancer Plans simply be adapted? “Please note, the idea is no longer to search for certain mutations but to sequence the entire genome. In this case, it would therefore be necessary to invest massively in latest generation sequencers but also in the training of professionals who will interpret this data. Even if artificial intelligence makes it possible to accelerate the processing of this information, we are potentially talking about sequencing 730,000 genomes per year!” explains Professor David Geneviève, president of the French-speaking association of clinical geneticists (University of Montpellier).
Several projects already launched must evaluate the medico-economic cost of such a project compared to conventional tests: benefit of early treatment for the child and his family (savings in terms of examinations, unsuitable treatments, and all the care “saved”…) versus a very significant initial financial investment.
The need for a list of diseases to look for
Should parents be asked to agree to such genetic testing? On this level, we can only be surprised by the fact that the law has already decided, avoiding prior information to parents. Even if we can assume that this choice is motivated by the concern for greater fluidity, this absence of upstream information raises questions3.
What are we looking for in the genome? If we take the DNN framework as it is defined in Europe: serious genetic diseases occurring in childhood that can be treated as well as those for which the quality of life can be improved.
But if we have all the genetic information, should we exclude from this research genetic diseases that appear late (such as Huntington’s disease), simple genetic predispositions and incurable diseases? Not all countries have the same answers to these questions.
Faced with these specificities, lists of diseases to be searched for are established by each country, even if it means revising them according to therapeutic or even ethical developments. “Several lists already exist in the United States, England, Australia with curable diseases for which treatment exists, diseases for which treatment can improve the quality of life… Each country, depending on its legislative framework, must establish one’s own” specifies Professor Geneviève. For other countries, no list and no guarantee as to the ethical framework…
Can the DPI model be transposable?
In Europe, pre-implantation diagnosis (PGD) is reserved for couples who have already had a seriously ill or deceased child due to a genetic disease (cystic fibrosis, myopathy, cancer linked to a genetic factor, etc.) or whose one of the parents carries a disease which they have a good chance of being able to transmit to their children.
In the context of medically assisted procreation, PGD makes it possible to reimplantation embryos not carrying this mutation – and only this one – to avoid the birth of a second affected child. There is no official list established beforehand but nearly 500 diseases are searched for in the 5 authorized centers (Montpellier, Nantes, Paris, Strasbourg and Grenoble)4.
PGD only allows you to search for the known mutation and there is no question of looking elsewhere. In 2020, the National Assembly voted against the expansion of PGD to the search for chromosomal abnormalities (PGD-A) – in this case the question was to extend the scope of this diagnosis to chromosome counting . Thus, embryos carrying trisomies could have been discarded during assisted reproduction.
Note that the framework is less restrictive in Belgium and in other countries of the European Union.
And in the event of discovery of unsearched mutations?
And what should we do if we detect undesired mutations despite everything? In Europe, we talk about “incidental data”. If they are hereditary, they can beyond the patient…