New Large-Scale Genetic Sequencing Effort to Identify Causes of Rare Developmental Disorders

February 2, 2015

A collaboration between the Wellcome Trust Sanger Institute, the UK Department of Health, and UK genetics services aims to identify genetic causes for undiagnosed developmental disorders and incorporate large-scale genetic sequencing into health care diagnosis and treatment. The project, Deciphering Developmental Disorders (DDD), currently involves 12,000 families that have been unable to receive a diagnosis with single gene or multi-gene testing of known disorders. The DDD project uses whole exome sequencing (WES), which sequences all the protein-coding genes to try to identify the causative gene or genes and mutations.

The DDD project has provided a diagnosis for about 30 percent of the first 1,000 families sequenced. Most of these mutations are de novo, or new mutations in the child’s genome and not mutations inherited from the parents. Many of these diagnoses are identifying mutations in the about 1,000 genes previously known to cause developmental disorders. Researchers are also examining changes in about 18,000 other genes to try to identify new disorders. So far, the project has identified 12 new genetic causes of developmental disorders by identifying multiple patients with shared mutations and symptoms, including two unrelated children who both had mutations in the polycomb group RING finger protein 2, or PCGF2, gene which codes for a protein previously known to be involved in embryo development, tumor development, and the immune system.The two children also had very similar symptoms and physical appearance. The shared symptoms, appearance, and mutations in the PCGF2 gene can now be considered a specific genetic syndrome. With each new genetic cause identified, the proportion of patients that can be diagnosed increases; these 12 new identified genetic causes has increased the number of participating families that can be diagnosed by 10 percent.

One of the key challenges of the DDD project is to filter out benign changes. Non-related changes are identified by comparing the patient’s symptoms to a database of all known developmental disorders. A second way is conducting “trio sequencing”, or WES for both parents and the child. Trio sequencing greatly reduced the number of changes that needed to be examined to reach a diagnosis.

Even with these advances, there are patients who will not receive a diagnosis through WES and comparing the findings to previously identified syndromes and to data from other UK participating families. The clinicians and researchers in the DDD project will place de-identified data on these undiagnosed patients in the DECIPHER database maintained by the Wellcome Trust Sanger Institute. Hopefully, international sequencing efforts will provide data enabling a future diagnosis.


The project will continue to recruit UK families through April 2015 for participation.


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