Genomics study provides diagnoses for over 5000 children

A long-running project has provided diagnoses for over 5000 children with rare developmental conditions and has identified 60 new genetic disorders.

The Deciphering Developmental Disorders (DDD) study began enrolling patients in 2011, predating the NHS Genomic Medicine service and the 100,000 Genomes project. An overview of findings published in the New England Journal of Medicine shows that the research provided a diagnosis for 41 percent of participants, and created a platform to connect clinicians whose patients had the same ultra-rare mutations.

'The families in our study were desperate for answers, which can make a huge difference to clinical management and quality of life,' said lead author Professor Caroline Wright from the University of Exeter. 'We worked with hundreds of clinicians and scientists, as well as thousands of patients to try to find those answers.'

Almost 13,500 families, across the UK and Ireland, joined DDD between 2011-2015. All families had one or more children with an undiagnosed, severe development disorder, that doctors thought was caused by a single gene mutation, but that NHS testing had been unable to identify.

Analysis of the data took place from 2014 to 2022, after which 41 percent of children received a diagnosis. In around three-quarters of those, the cause was a de novo mutation – a new change in the genome not inherited from either parent.

Children whose genomes were analysed alongside genomes of both parents (known as a trio) were almost five times more likely to receive a diagnosis than children whose genomes were analysed alone. Children whose conditions were most severe also had a higher chance of receiving a diagnosis, as did children who were the only affected person in their family.

Children with non-European ancestry had a lower chance of diagnosis – particularly those of African descent. The researchers acknowledged several influencing factors including fewer children in this group being part of trios, and lack of ancestry-matched control subjects for comparison.

The DECIPHER database, developed as part of the project, was used to ascribe how likely genetic variants were to cause disease and how they related to the patient's symptoms. It also allowed clinicians across the globe who have patients with similar ultra-rare mutations and symptoms to connect, allowing new disorders to be described and catalogued.

'Embedding a powerful informatics platform at the heart of this study facilitated the collaboration with families, clinicians and scientists engaged in the project, and played an essential role in its diagnostic success and in the discovery and ultimately treatment of new causes of rare genomic disease,' said the study's clinical lead Professor Helen Firth from Cambridge University Hospitals NHS Foundation Trust.

The DDD study is a collaboration between the Wellcome Sanger Institute in Cambridge, and the NHS and has already resulted in over 290 publications. Findings from the study have informed approaches being adopted by the NHS Genomic Medicine Service.