New genomic testing provides vital diagnosis for severely ill babies

More than a third of severely sick babies referred for rapid whole genome sequencing receive vital genetic diagnosis in latest study across the East of England.

Results from the latest Cambridge genomic study supported by NIHR Cambridge BRC and NIHR BioResource, confirm rapid whole genome sequencing (WGS) as an effective early test to aid diagnosis in severely ill children.

WGS can determine variations in any part of the genome. By looking at all the genes in the genome it is possible to uncover disease-causing changes with a single test. This is important as some of the findings can be in unexpected genes.

Building on the findings from the Next Generations Children’s Project (2019), over 500 seriously ill children and their parents across the East of England – average age of 8.5 months – were recruited from several paediatric service settings. The aim was to provide greater insight into the benefits of rapid WGS compared to other routine genetic tests in areas such as neonatal intensive care units (NICU), paediatric intensive care units (PICU), paediatric neurology clinics and clinical genetics clinics.

Researchers worked hand in hand with scientists at East Genomic Laboratory Hub, based in Addenbrooke’s hospital, Cambridge to deliver the testing.

Findings illustrate that children in all four settings benefited from WGS testing at an early stage of their diagnoses, with patients referred from neurology having the highest percentage of confirmed diagnosis (46%), 31 % in PICU and 25% in NICU. Diagnostic rates were highest in patients with neurodevelopmental delay, hypotonia, seizures or suspected mitochondrial disorder.

In 90% of cases, both parents contributed DNA samples alongside their child in tests known as a ‘trio analysis’, which is now the gold standard test within the NHS. Comparing patient’s and parents’ DNA changes allows for identification of new information on known disease-causing genes and for the discovery of several new genes not suspected prior to testing.

Professor Lucy Raymond - Integrative Genomics theme lead

Professor Lucy Raymond, Professor of Medical Genetics and Neurodevelopment at the University of Cambridge and Honorary Consultant at Cambridge University Hospitals NHS Foundation Trust, pictured right, commented: “We found that overall one in three patients received a vital diagnosis and importantly more than one in five diagnoses would have been missed without the broad analysis carried out by WGS testing. Diagnoses that were identified included spinal muscular atrophy (SMA) and other neurodegenerative conditions including some rare epilepsies, which are now eligible for precision medical therapies in the NHS.

“Finding a diagnosis changes management, stops unnecessary tests, and reassures families that everything has been done that can be done for their child.

“Rapid parent and child WGS (or trio) analysis is an excellent single test suitable for many patients as soon as possible on admission to hospital or specialist clinic. However, this must be supported by sufficient training for clinicians as well as scientific expertise for robust analysis of results.”

Many genes that can cause a rare disease have not yet been identified, so a negative result – or an unconfirmed diagnosis – does not mean a condition isn’t genetic. It does however highlight the need to keep looking at the genome to find new genes that cause disease and to help clinicians and families in the future.

Professor Raymond added: “Continuing follow-up of families within national genomic research databases such as the NIHR Bioresource or the National Genomics Research Library enables involvement in further social and health research and new genomic discoveries alongside potential recruitment to clinical trials beneficial to patients.”

Professor David Rowitch - Paediatrics theme lead

Professor David Rowitch, Paediatrician (neonatology) and developmental neuroscientist and NIHR Cambridge BRC paediatric theme lead, pictured left, said: “The study highlights that the burden of genetic disorders in paediatric inpatient and specialist clinic settings is much higher than previously suspected. The finding that children in neurology have a 46% rate of diagnosis by WGS is likely to be quite surprising to many clinicians.”

“It also shows that frequent re-analysis of patient WGS data improved the diagnostic rate as new genes were confirmed and published by other sources. Moreover, by sharing data and contributing to the international rare disease endeavours, other patients can hopefully receive a potential diagnosis.”

Dr Topun Austin, Consultant Neonatologist, Neonatal Intensive Care Unit CUH commented: “The time taken to reach a diagnosis in these children can often be prolonged, requiring multiple tests and consultations. Rapid trio WGS in the NICU has enabled newborn infants with complex illness to be diagnosed at an earlier stage, which can significantly impact on their management.

“This study supports the 2019 research findings and provides further evidence of the value of rapid WGS to staff and patients. The NHS now provides rapid sequencing across all NICU and PICUs in the UK clearly showing how research can make a meaningful impact on clinical care”.

Jo Balfour, Managing Director, Cambridge Rare Disease Network commented: “It is the most worrying time for a family when their child is unwell and the reason is unknown. Whilst rapid WGS does not promise a clear diagnosis for every child with a rare health condition, research that supports advances in genomic testing to help more children and their families is welcome”.

The research was supported by the NIHR Cambridge Biomedical Research Centre, NIHR Rare Disease Bioresource, The Rosetrees Trust, and Isaac Newton Trust. Thanks also to Health Education England’s Higher Specialist Scientist Training programme which enabled East GLH staff time on this project. 

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