Large-scale population studies needed to reduce risks from newborn genome screening

New research from large population studies provides invaluable evidence on genome screening of newborn babies to reduce risks from overdiagnosis. The authors conclude that further studies are needed before such screening is rolled out.

A team at the University of Exeter is publishing a series of papers which highlight the risks that screening can pose and call for action to minimise harms to families. Funded by the Medical Research Council and National Institute for Health and Care Research (NIHR) Exeter Biomedical Research Centre, the research is being presented at the European Human Genetics Conference (June 16), with three papers so far published in the European Journal of Human Genetics special issue on DNA in public health screening programmes.

Newborn genome screening pilot studies are increasingly being rolled out in countries including the UK, and involve determining the entire sequence of a baby’s genetic code and interrogating it for hundreds of potentially treatable conditions. The research team cautions that most genetic studies to date have been carried out in groups of people who already have a condition, or are in a high-risk family. This means that the known risk of a genetic variant causing a disease (known as penetrance) is often higher than the actual risk in the general population.

To put this to the test, the Exeter team has analysed genetic variants previously found to cause disease, using large datasets of the general population, including nearly a million volunteers in either UK Biobank or All of Us. Focussing on more than 50 genes across 15 diseases included in largescale trials for newborn genome screening, the team looked for the variants, and whether people who carry them have the disease.

Dr Leigh Jackson said, of the University of Exeter Medical School, said: “We found that in most cases, although there is a link between the genetic variants and the disease, it’s weaker than previous research has suggested. This is because most research is conducted in people who already have a disease or are at high risk. The actual risk is often lower if you’re looking at the general population, as would be the case if you applied this risk to newborn screening.”

The team’s published research  found that the biggest risk of overdiagnosis arose when the risk of disease stems from a loss of just one of the two copies of a gene. However, the picture was mixed and for other conditions, their upcoming research will show that where  both copies of the gene need to be lost to cause disease, the evidence suggests a lower risk of overdiagnosis.

Professor  Caroline Wright, of the University of Exeter Medical School, said: “The UK is leading the way on newborn genome screening and the world is watching. We urgently need the best evidence to ensure we get this right. The benefits of a successful programme will be profound, but we need to be aware of the risk of overdiagnosis based on current evidence. Being told your baby is at high risk of developing disease has a massive impact on families – we need to ensure we use the most accurate risk estimates possible in order to provide the best care.”

The three papers published so far in the European Journal of Human Genetics are:

Revisiting penetrance in an era of genomic screening: https://www.nature.com/articles/s41431-026-02101-1

Reduced penetrance of COL1A1/2 pathogenic variants linked with osteogenesis imperfecta: analysis of a large population cohort: https://www.nature.com/articles/s41431-026-02118-6

Uncovering apparent incomplete penetrance of TSC1/TSC2 variants: Insights from multiple population cohorts and implications for newborn screening: https://www.nature.com/articles/s41431-026-02107-9

And another two are in the preprint server medRxiv:

Prevalence and Penetrance of Heritable Retinoblastoma in Two Adult Population Cohorts: Implications for genomic newborn screening: https://www.medrxiv.org/content/10.64898/2025.12.16.25342350v1

Investigating penetrance of severe combined immunodeficiency variants in an adult population cohort: implications for genomic newborn screening, https://www.medrxiv.org/content/10.64898/2026.02.17.26346478v1