Genome Analysis Study to Aid Diagnosis of Rare Developmental Disorders

The program has brought together clinicians in the 24 Regional Genetics Services throughout the United Kingdom and researchers at the Wellcome Trust Sanger Institute, which played a leading role in sequencing the human genome. The DDD study involves experts in clinical, molecular, and statistical genetics as well as in ethics and social science.

The first paper to be published under the auspices of the DDD program reported results from a study of 1,133 children with severe, undiagnosed developmental disorders, and their parents, using a combination of exome sequencing and array-based detection of chromosomal rearrangements. The investigators reported discovering 12 novel genes associated with developmental disorders. These newly implicated genes increased by 10% (from 28% to 31%) the proportion of children that could be diagnosed. All of the newly diagnosed developmental disorders were caused by de novo mutations, which were present in the child but not in their parents' genomes.

DDD's nationwide secure data-sharing network made it possible to find and compare these rare disorders. For example, for four of the 12 newly identified genes, identical mutations were found in two or more unrelated children living hundreds of miles apart. In another example, two unrelated children, both with identical mutations in the PCGF2 (Polycomb group RING finger protein 2) gene, which is involved in regulating genes important in embryo development, were found to have strikingly similar symptoms and facial features. This discovery enabled the certification of a new, distinct dysmorphic syndrome.

"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," said contributing author Dr. John Burn, professor of clinical genetics at Newcastle University (United Kingdom). "This data-set becomes more effective with each diagnosis and each newly identified gene."

The study was published in the December 24, 2014, online edition of the journal Nature.

Related Links:
Wellcome Trust Sanger Institute
Newcastle University