Project finds 12 new genetic causes of developmental disorders

Nationwide, genome-wide sequencing provides diagnoses for rare conditions

Deciphering Developmental Disorders

The map shows locations of children with three of the newly identified developmental disorders. The location of the mutations on the genome is also shown.

DDD, which is a collaboration between the NHS and the Wellcome Trust Sanger Institute and is funded by the Department of Health and Wellcome Trust through the Health Innovation Challenge Fund, worked with 180 clinicians from 24 regional genetics services across the UK and the Republic of Ireland to analyse all ~20,000 genes in each of 1133 children with severe disorders so rare and poorly characterised that they cannot be easily diagnosed using standard clinical tests. The benefits of diagnosis include improving clinical management, helping parents obtain support, informing reproductive choice and providing a molecular basis for the disorder, which is the starting point in the search for new treatments.

The DDD project works by collecting together clinical information in a database along with the genetic variants from each patient’s genome. If patients who share similar symptoms also have variants in common, it helps to narrow down the search for causative mutations across the genome. However, this can be challenging, since the chance of having a particular type of mutation can be as low as one in fifty million. DDD’s nationwide secure data-sharing network has made it possible to find and compare these incredibly rare disorders; in fact, for four of the 12 newly identified genes, identical mutations were found in two or more unrelated children living hundreds of miles apart.

“Working at enormous scale, both nationwide and genome-wide, is critical in our mission to find diagnoses for these families. This project would not have been possible without the nationwide reach of the UK National Health Service, which has enabled us to unite a number of families who live hundreds of miles apart but whose children share equivalent mutations and very similar symptoms.”

Dr Helen Firth An author from the Department of Clinical Genetics at Addenbrooke’s Hospital and Clinical Lead for the DDD study

In one example, two unrelated children, both with identical mutations in the gene PCGF2, which is involved in regulating genes important in embryo development, were found to have strikingly similar symptoms and facial features. This constitutes the discovery of a new, distinct dysmorphic syndrome.

All of the newly discovered developmental disorders were caused by new, ‘de novo‘, mutations, which are present in the child but are not in their parents’ genomes. The DDD project has shown that it is critical to use, where possible, genetic data from parents, most of whom do not have a developmental disorder, to help filter out benign inherited variants and find the cause of their child’s condition.

“The DDD study has shown how combining genetic sequencing with more traditional strategies for studying patients with very similar symptoms can enable large-scale gene discovery. This data-set becomes more effective with each diagnosis and each newly identified gene.”

Professor Sir John Burn Professor of Clinical Genetics at Newcastle University

Originally, the DDD project focused on applying array technology to screen genes for deletions or duplications that cause the patient’s disorder. However, this strategy enabled researchers to find a diagnosis for only 5 per cent of patients. Improvements in sequencing technology have allowed DDD to use genome-wide ‘exome’ sequencing that searches through all protein-coding genes for all classes of genetic variants. This approach produces 100 times more data but delivers a diagnosis for 30 per cent of patients.

“The success of DDD has provided a valuable test bed for Genomics England. This research has shown that the Government’s commitment to sequencing 100,000 genomes can produce powerful data that will make a real difference to genetic research as well as to clinical diagnostics and treatment.”

Professor Mark Caulfield Chief Scientist for Genomics England Limited

Nonetheless, some DDD children will not be able to be diagnosed by looking at data from UK patients in isolation, and so to identify similar patients from around the world DDD is sharing limited anonymised genetic and clinical data on these undiagnosed DDD children through the DECIPHER database (https://www.deciphergenomics.org). Researchers hope that the project will inspire more clinical and research programmes around the world to deposit data in the DECIPHER database to pinpoint more genetic causes of developmental disorders and improve diagnostic rates internationally.

“There is a clear moral imperative for both clinical testing laboratories and research studies to share this information globally. DDD and DECIPHER have demonstrated that large-scale data sharing can give families the diagnoses they so urgently need; diagnoses that simply cannot be made by looking at the data in isolation.”

Dr Matt Hurles Senior author and principal investigator on the DDD project from the Sanger Institute

More information

Funding

Generation Scotland has received core funding from the Chief Scientist Office of the Scottish Government Health Directorates CZD/16/6 and the Scottish Funding Council HR03006. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund [grant number HICF-1009-003], a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute [grant number WT098051]. The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network.

Participating Centres:

A full list of participating centres can be found on the paper.