Project pinpoints 12 new genetic causes of developmental disorders

The first results to emerge from a nationwide project to study the genetic causes of rare developmental disorders have revealed 12 causative genes that have never been identified before. The Deciphering Developmental Disorders (DDD) project, the world's largest, nationwide genome-wide diagnostic sequencing programme, sequenced DNA and compared the clinical characteristics of over a thousand children to find the genes responsible for conditions that include intellectual disabilities and congenital heart defects, among others.

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," explains Dr Helen Firth, an author from the Department of Clinical Genetics at Addenbrooke's Hospital and Clinical Lead for the DDD study. "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."

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.