The news that the Greek government has entrusted newborn screening to private organisations raises many concerns. Newborn screening is a vital public health initiative, and significant efforts are being made to improve the effectiveness and sustainability of programmes across Europe. But no such programme can be effective without significant public participation, and this can only be achieved through consultation at every step along the road. This has not been the case in Greece, where there has been no consultation with families or others, yet their compulsory participation in the scheme has been implied.

The application of wide-range genetic testing in newborns is in the early stages of research and its benefits and challenges still largely unknown. Adopting such a protocol outside a research framework is irresponsible.  Whilst there is public health research that can lawfully be carried out without the consent of participants, in public emergencies, for example, this type of project does not fit into that category.

ESHG believes that all stakeholders should be involved in planning and deliberating any population screening proposal. Clear and understandable information on the aim of the research, if and how results would be returned, conditions under which data would be held, and the accountability and legal obligations of the research team should be made available. It is also essential that the public should be told the precise conditions under which the companies will use the data and what would happen to them in the event of a takeover, bankruptcy, or any other unexpected event in the future.

We are concerned that a lack of transparency could affect the trust of the public in newborn screening and in healthcare more widely - and not just in Greece. We have seen how mistrust in vaccination, for example, has spread quickly all over the world. We understand that the agreement with the private companies has been put on hold, and we hope that the government will now undertake open consultation with all those likely to be affected in the future before proceeding further.

Milan, Italy: Pharmacogenomics studies how individuals respond to drugs based on their genetic code. Using that knowledge to guide prescribing in routine care could lead to better outcomes for patients and save money for health systems.

Generating pharmacogenomic data in the laboratory is relatively straightforward, but a major challenge is making that information available to frontline healthcare professionals in a clinically relevant format and timeframe. This has meant that, to date, only a limited numbers of patients have been able to benefit from such individually optimised treatments.

Dr John McDermott, NIHR Academic Clinical Lecturer at the University of Manchester, Manchester, UK, will describe to the annual congress of the European Society of Human Genetics today (Tuesday) how he and colleagues, as part of the NHS-England Network of Excellence for Pharmacogenomics & Medicines Optimisation, have pioneered an approach to integrate genomic data into electronic health records in both GP practices and hospitals. This means that patients’ genomic data can be made available to help select the safest and most effective treatment for everyone, irrespective of where they are in the health system. 

Pharmacogenomics is fundamentally different from rare disease and cancer genetics in that it has relevance across a patient’s life, each time they require a medicine. But the professionals handling the data are unlikely to have had extensive training in interpreting this complex genetic information. The team based in Manchester, supported by the NHS England Genomics Unit, have developed a novel informatic approach that enables genomic data to be presented to clinicians, directly in their electronic health record, without disrupting normal clinical practice. 

“Our solution can work with many commonly used genetic testing platforms and all the major electronic healthcare record systems used globally. This means that healthcare professionals need not worry about interpreting genetic reports, instead they receive contextualised guidance within their existing systems as part of the normal workflow,” says Dr McDermott.

The PROGRESS programme has recruited patients from 20 sites across England following prescription of common medicines - statins, opioids, antidepressants, and proton pump inhibitors - and pharmacogenomic guidance was returned, integrated into the electronic healthcare record. The proportion of patients with an actionable variant related to their medicine was recorded, along with prescription amendments, turnaround times and compliance with guidance.

An interim analysis of the first 500 participants showed that pharmacogenomic guidance had been provided to all patients, with a median turnround time of seven days. A pharmacogenomic result related to the prescription of common medications was found in 95% of participants, and just over one in four study participants had their prescription adjusted to a safer or more effective treatment.

Large-scale interventions like this need to be justified from a health economic perspective, Dr McDermott says. “There have been several studies showing the potential value of pharmacogenomics, which have typically focussed on specific drugs, specific genes, and specific clinical scenarios. For example, the UK's National Institute for Health and Care Excellence (NICE) have recently recommended that all patients who have had a stroke or a transient ischaemic attack (TIA) should undergo pharmacogenomic testing to guide the choice of antiplatelet therapy.  This was based on a health economic assessment which demonstrated a potential value to the health system of hundreds of millions of pounds in prevented strokes and gained quality of life.”

Having demonstrated that genomic data can be integrated into routine care pathways and successfully inform clinical decision making, the researchers now intend to leverage routinely- collected healthcare data at scale to investigate how these prescribing changes are impacting healthcare utilisation and establish whether the intervention reduces the need for further appointments, attendance in emergency departments, and overall prescribing costs. 

“It was notable how frequently clinicians chose to follow the pharmacogenomic prescribing guidance. We think this reflects the fact that healthcare professionals had the data presented to them just like they would with any other biomarker. Prescribing is often adjusted based on things like renal function, and so we designed this intervention in a very similar way,” says Dr McDermott. “We hope that in future individual pharmacogenomic profiling will become equally integrated and commonplace. Our study has shown that this is possible, and now we intend to show that it will also be beneficial from a health economic point of view.”

Professor Dame Sue Hill, Chief Scientific Officer and Senior Responsible Officer for Genomics at NHS England, said: “This pioneering study shows how we can transform patient care through innovative approaches to personalised medicine. Seeing that more than a quarter of study participants had their prescriptions adjusted to safer or more effective treatments underscores the real difference this approach can make to people's lives. Pharmacogenomics will be a key part of the NHS Genomic Medicine Service in the future.”

Chair of the conference Professor Alexandre Reymond said: “This research concerns us all, since every one of us has a handful of pharmacogenomic actionable variants in our genome. The use of a specific, genomically targeted treatment can greatly reduce the risk of a bad outcome related to these variants.”

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The research was funded by NHS England.

Talk no. C36.05 Integrating pharmacogenomic guided prescribing into primary care: The NHS PROGRESS study

Note:  When obtaining outside comment, journalists are requested to ensure that their contacts are aware of the embargo on this release.

Milan, Italy: Neuropathy, a disorder in which damage to nerves can impair sensation and movement, has many causes, including infection¹. Now, researchers from the UK have identified distinct genetic changes in a newly-discovered neuropathy and believe that their work will provide insights into the causal mechanism and why some previously healthy people develop neuropathies after infection whereas others do not.

Dr Rob Harkness, a postdoctoral research Fellow at the University of Manchester, Manchester, UK, will tell the annual conference of the European Society of Human Genetics today (Monday) how the researchers were alerted to the case of a child in intensive care who had been fit and well until seven months old. Following a mild fever and rash she became very floppy and weak, needed help with her breathing and died before reaching her first birthday. A similar pattern had affected two of her elder brothers.

“At that point we undertook a genetic discovery study. We identified a change in a gene that we thought was likely to be the cause but it wasn’t until around ten years later that we identified a second affected family with changes in the same gene with a similar clinical history – rapid neuropathy following a mild infection. Now we know of 12 affected families with changes in this gene,” says Dr Harkness.

The physical effects caused by changes in this gene are similar to those seen in patients with the neuropathy called Guillain-Barré syndrome, which can also be triggered by infections including Epstein-Barr virus and the bacterium campylobacter. The condition can start in people who are completely healthy and cause them to develop weakness of the legs that can spread to the whole body, including affecting their breathing.

“We hope that our discovery will provide insights into the mechanisms that cause the problem. The experiments we have undertaken on cells from patients show similar features to those seen in motor neurone disease (MND), and we may be able to use knowledge gained in research on MND to help patients affected by this newly-defined condition, and vice versa,” Dr Harkness says. “Unfortunately, there are currently no effective prevention strategies for such neuropathies, but our greater understanding of the causes of these conditions will be the first step towards developing treatments.”

The new results allow a rapid, accurate diagnosis rather than numerous lengthy and expensive investigations. They will already permit preconception testing of individuals at risk of having an affected child so that this can inform their future reproductive choices. Since the researchers began to publicise their work, more families across the world have been identified, leading them to believe that the rare condition is more common than they originally believed. They are continuing their work by making nerves from skin cells donated by affected people, allowing them to understand why this disorder affects the nervous system specifically, and to test potential treatments. “We are also mirroring these studies using fruit flies,” says Dr Harkness.

“Our hypothesis that there would be a change to a single gene responsible for this particular neuropathy was correct. However, we could not predict which gene it would be and what its role was. Now we know that the gene we identified is vital in controlling how proteins and nucleic acids move between the cell nucleus and the cytoplasm, the gelatinous liquid filling the inside of the cell. This movement is very sensitively controlled and extremely susceptible to stress, temperature and infection in patients with this condition, and when it affects the nerves, they cannot be repaired.”

Chair of the conference Professor Alexandre Reymond said: “This is a textbook example of gene-environment interaction. All of us carry on our respective genomes small alterations (genetic variants) that put us at risk of environmental changes, in this case specific infections.”

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The research was funded by the rare disease organisation LifeArc and the Manchester NIHR Biomedical Research Centre

1.Neuropathy may appear following infection with Clostridium botulinum, which causes botulism, West Nile virus, which causes a disease resembling poliomyelitis, and a number of other bacteria and viruses, including Covid-19.

Talk no. C29.02: Genetic risk of axonal neuropathy following infection

Milan, Italy: A new, rapid testing method will greatly help the diagnosis of rare diseases in babies and children, according to research to be presented to the annual conference of the European Society of Human Genetics today (Monday). While rare genetic diseases are uncommon, as their name suggests, there are more than 7,000 types of disease caused by mutations in more than 5,000 known genes, affecting approximately 300 million individuals worldwide. Currently about half of all patients with a suspected rare disease remain undiagnosed and existing testing methods for undiagnosed conditions are typically slow, targeted to a specific disease, and not always sensitive. This can mean years, or even decades, of inconclusive investigations and invasive tests, causing distress and uncertainty for affected families.

Dr Daniella Hock, a Senior Postdoctoral Researcher at the University of Melbourne, Australia, will present to the conference how she and her team have been able to develop a blood-based method of analysing thousands of proteins in a single, untargeted test. The DNA sequence of most genes is the code to produce proteins, the molecular machines of our cells and tissues. The test is unique as it sequences proteins rather than the genes themselves, and the data can help understand how changes in the gene sequence affect its corresponding protein’s function and lead to disease. The test is applicable to potentially thousands of different diseases, and it can even be used to detect new ones by providing the evidence needed to confirm that a genetic change is the likely cause of the disease. As well as being fast, the proteomic¹ test is minimally invasive, requiring only 1ml of blood from infants and with results available in under three days for patients in acute care. “When the test is also performed on blood samples from parents we call it trio analysis. In recessively inherited conditions, this helps considerably in differentiating between carriers, who only have one copy of the defective gene, and the affected individual who carries two copies,” she says.

For the patient, such a molecular diagnosis means rapid access to appropriate treatment, if available, a prognosis, and an end to numerous, sometimes invasive tests. For families, a diagnosis can mean access to reproductive options to prevent the occurrence of disease in future pregnancies via prenatal or preimplantation genetic testing. And for healthcare systems, replacing a battery of targeted tests by a single analysis should lead to reduced healthcare costs, not just by reducing the testing required for a diagnosis, but also by being able to offer appropriate care at an early stage.

“A recent study² carried out in collaboration with the Melbourne School of Population and Global Health revealed that implementing our test in a clinical setting would have a similar cost to that of the current test used to diagnose rare mitochondrial disease, with the advantage that our test can potentially diagnose thousands of other diseases,” says Dr Hock. “Our new test can identify more than 8,000 proteins in peripheral blood mononuclear cells (PBMCs) covering more than 50% of known Mendelian and mitochondrial disease genes, as well as enable us to discover new disease genes.”

The researchers hope that their test will become part of standard diagnostic procedure for rare and other genetic diseases in clinical labs. “The ability to use so little blood from infants and to produce robust results with a rapid turnaround time has been revolutionary to families. Moreover, the use of familial samples for trio analysis greatly improves the differentiation between carrier and affected individuals with higher confidence, and that has exceeded our initial expectations. We believe that the use of this test in clinical practice will bring considerable benefits to patients, their families and to healthcare systems by reducing the diagnostic time” Dr Hock concludes.

Chair of the conference Professor Alexandre Reymond said: “Non-invasive agnostic approaches such as genome sequencing and protein analysis will allow us to reach a diagnosis more rapidly in the future. They will also permit the solving of previously unsolvable cases, thus helping families worldwide.”

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The research was supported by the Australian National Health and Medical Research Council (NHMRC) grant (1140906), Investigator Fellowship (2009732), Australian Medical Research Future Fund Genomics Health Futures Mission grant (2016030), Australian Medical Research Future Fund National Critical Research Infrastructure grant (NCRI000043) and The Mito Foundation research equipment grant and large research equipment grant.

1.A proteomic test studies the structure and function of proteins, including their expression, abundance and how they interact with each other inside cells.

2. https://pubmed.ncbi.nlm.nih.gov/39609890/

Talk no. C24.03: Trio PBMC proteomics for rapid variant functionalisation in the diagnosis of rare diseases

Milan, Italy: Children born before 37 weeks of gestation have a considerably increased risk of dying before they reach the age of five. Predicting the risk of preterm birth (PTB) and hence implementing preventive strategies is complicated by the heterogeneity of the condition, the many unknown mechanisms involved, and the lack of reliable predictive tools. Now, however, researchers have been able to show that blood cell-free RNA (cfRNA) signatures can predict PTB over four months before delivery date, the annual conference of the European Society of Human Genetics will hear today (Sunday).

Dr Wen-Jing Wang, an associate researcher at BGI Research in Shenzhen, China, together with team leader Professor Chemming Xu from the Obstetrics and Gynaecology Hospital of Fudan University, Shanghai, China, and colleagues analysed blood plasma samples from 851 pregnancies (299 PTB cases and 552 controls) at about 16 weeks gestation to identify cfRNA markers associated with spontaneous PTB, and found significant alterations in cfRNA between PTB and birth at term. The study included both preterm births with intact membranes and premature rupture of membranes (when the waters break before labour starts), with fewer than 3% having a prior preterm birth.

“Being able to detect these predictive signals over four months suggests early biological priming for PTB, far earlier than current clinical recognition,” she says. “This extended window could revolutionise prevention strategies.”

Annually, about 13.4 million newborns worldwide are delivered prematurely, accounting for approximately one in ten of all live births. Nearly one million of these preterm infants die each year, and PTB remains the primary cause of mortality in children under five. Because children born preterm have immature organs that are not yet prepared for life outside the womb means that they will have a far higher risk of complications than those born at term. This can lead to a range of health issues such as respiratory problems, jaundice, feeding difficulties, and infections. Long-term health problems for these children include cerebral palsy, epilepsy, and blindness, and impose substantial emotional and financial burdens on families.

“Practically, our method uses the same blood draw timing as routine Non-Invasive Prenatal Testing (NIPT), enabling dual testing. Current cfRNA sequencing costs are similar to NIPT pricing, but future optimisation using targeted qRT-PCR panels could reduce expenses significantly. This creates a potential route to both monitoring patients at high risk and for wider population-level screening,” says Dr Wang.

Unlike static DNA or immune-focused cellular biomarkers, circulating RNA can provide dynamic, tissue-specific insights. The researchers say that they have already observed distinct patterns – infection and inflammation signatures in preterm cases with rupture of the membranes as opposed to dysregulation of metabolism and trophoblasts¹ in intact membrane cases, and that these findings were corroborated by clinical parameters. “The liquid biopsy approach could transform our understanding and management of pregnancy complications,” says Dr Wang.

Before this diagnostic technique can be used more widely, the researchers say that standardised protocols for sample handling need to be developed, given RNA’s instability compared with DNA. Prediction algorithms need to be developed in diverse population studies, and the causes of different PTB subtypes explored to be able to guide targeted interventions. The team is pursuing these goals and seeking to collaborate with other institutions in order to accelerate the use of their findings in clinical practice.

Chair of the conference Professor Alexandre Reymond said: “Advances in sequencing and analysis technologies are now offering many new diagnostic possibilities. This is a fascinating example of the use of sequencing readouts to evaluate risk, rather than assessing genetic background to assess predisposition.”

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1.Trophoblasts are cells forming the outer layer of a blastocyst, which provides nutrients to the embryo, and develops into a large part of the placenta. They are formed during the first stage of pregnancy and are the first cells to differentiate from the fertilized egg.

Talk no. C21.06: Early prediction of preterm birth with cell-free RNA

Funding: This work was supported by the National Key R&D Program (2023YFC2705600), National Natural Science Foundation of China (81901495) and Science, Technology and Innovation Commission of Shenzhen Municipality (JCYJ20170412152854656).

Milan, Italy: A case in which a sperm donor was later found to be carrying a cancer-causing pathogenic variant in his gametes has highlighted the problems of regulating gamete donation at European and international level, the annual conference of the European Society of Human Genetics will hear today (Saturday). Dr Edwige Kasper, a specialist in genetic predisposition to cancer at the Rouen University Hospital, Rouen, France, will say that the lack of cross-border regulation in Europe can result in the multiple use of gametes in families and risks inbreeding and the abnormal dissemination of inherited diseases.

Towards the end of 2023, Dr Kasper’s laboratory was contacted by a French clinician who said that one of his patients had received a letter from a private sperm bank located in Europe, alerting her to the identification of a ‘variant of unknown significance’ in the TP53 (tumour protein 53) gene in less than 50% of the donor’s gametes. TP53 provides instructions for making a tumour suppressor protein, keeping cells from growing and dividing too fast or in an uncontrolled way. The letter said that the donor was in good health, but that his biological children could be at risk of Li-Fraumeni syndrome, a rare inherited disorder that predisposes to the development of cancers. Some of these children had already developed leukaemia and non-Hodgkin’s lymphoma, and this led to any use of the donor’s gametes being definitively blocked.

“I analysed the variant using population and patient databases, computer prediction tools, and the results of functional trials, and came to the conclusion that the variant was probably cancer-causing and that children born from this donor should receive genetic counselling,” says Dr Kasper. After discussion with French networks, the researchers presented these cases at a meeting of the European Reference Network on genetic tumour risk syndromes (GENTURIS) in 2024. Simultaneously, a number of Genetics and Paediatric Departments across Europe were investigating their own cases, leading to 67 children from 46 families in eight European countries being tested, with the variant being found in 23 of them and cancer found in ten to date.

Alterations in the TP53 gene cause Li-Fraumeni syndrome, one of the most severe inherited predispositions to cancer that is characterised by a broad spectrum of tumours at an early age. The affected children, born between 2008 and 2015, are being closely monitored to detect the first signs of cancers. “The follow-up protocol involves whole-body MRI scans, MRI scans of the brain and, for adults, of the breast, ultrasound examination of the abdomen, and a clinical examination by a specialist. This is heavy and stressful for carriers, but we have seen its effectiveness in that it has enabled early detection of tumours and thus improved patients’ chances of survival,” says Dr Kasper. “Because animal models of Li-Fraumeni syndrome have shown that exposure to genotoxic chemotherapy or X-rays accelerated tumour development, these children should avoid radiation-based imaging techniques such as mammography and PET scans, if possible.”

The researchers are continuing to identify cases of European children born from the same donor. “Although the variant would have been practically undetectable in 2008 when the individual started to donate sperm, there are many things that could have been and still need to be improved,” says Dr Kasper. “Some fertility clinics have refused to provide information to the families concerning the variant because they wanted the children to be tested in their own laboratories. There is a major issue here concerning a lack of harmonised regulation across Europe.”

Currently, laws on sperm donation differ from one European country to another. Private sperm banks usually limit donation from one donor to 75 countries worldwide. The law in France sets a limit of ten births per donor. However, in addition, there can be up to  15 births in Germany and in Denmark, and in the UK the same donor may be used for 12 and 10 families, respectively. At a European or international level this can represent a large number of births.

“My advice to French parents would be to favour a medically assisted procreation procedure in France, where donation is voluntary, anonymous, and free. The latter may explain the difference between parents’ needs and the lack of resources,” says Dr Kasper, “but it is very much safer. While donor examinations are routinely conducted in many countries, in France, gamete donation is medically supervised for both donors and recipients. Importantly, any suspicion of a genetic disorder must be promptly reported and investigated. Above all, each donor is limited to a maximum of ten births across the country, and the import or export of gametes may only be requested by an approved centre and is subject to authorisation from the Agence de la Biomédecine. “The fact that the case in point is very rare does not mean that it will not reoccur, and gonadal mosaicism – where one or more groups of cells possess a different genetic makeup - has  previously been reported in a sperm donor with reference to neurofibromatosis type 1. We need proper regulation at European level to try to prevent it happening again, and to implement measures to ensure a worldwide limit on the number of offspring conceived from the same donor.”

Chair of the conference Professor Alexandre Reymond said: “While current legislation on assisted reproduction usually does not cross borders, this is a good example of why wider oversight is needed.  But for now, what we learn in genetics in one country can help future parents everywhere.”

Talk no. C13.06: Multiple European children born with cancer predisposition following recurrent sperm donation from a mosaic TP53 carrier

The discrepancy between the numbers in the abstract and those in the press release can be explained by the fact that numbers were updated after abstract submission.