Sequencing DNA and comparing the clinical characteristics of over 1,000 children, researchers have identified 12 new genes responsible for rare developmental disorders such as intellectual disabilities and congenital heart defects, among others.
The Deciphering Developmental Disorders (DDD) project in Britain worked with 180 clinicians from 24 regional genetics services across Britain and Ireland to analyse approximately 20,000 genes in each of 1,133 children.
The children had severe disorders so rare and poorly characterised that they could not be easily diagnosed using standard clinical tests.
“Working at enormous scale, both nationwide and genome-wide, is critical in our mission to find diagnoses for these families,” said one of the study authors Helen Firth from Addenbrooke’s Hospital.
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,” said John Burn, professor of clinical genetics at Newcastle University.
“This data-set becomes more effective with each diagnosis and each newly identified gene,” Burn added.
The researchers used genome-wide “exome” sequencing that searches through all protein-coding genes for all classes of genetic variants.
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,” says Professor Mark Caulfield, Chief Scientist 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.”
The project is a collaboration between the NHS (UK National National Health Service) and the Wellcome Trust Sanger Institute.
The findings appeared in the journal Nature.
The Deciphering Developmental Disorders Study; The Deciphering Developmental Disorders Study. Large-scale discovery of novel genetic causes of developmental disorders. Nature. 2014 Dec 24. doi: 10.1038/nature14135. [Epub ahead of print]
PubMed PMID: 25533962.