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What are developmental disorders and syndromes?

Developmental disorders are important conditions defined by the fact that the cause of each begins during embryonic development. Developmental disorders such as intellectual disability, infantile epilepsy and malformations (congenital heart disease, small/absent eyes etc) are frequent causes of chronic disability during childhood and many are caused by changes in the DNA sequence of a specific gene. In some children who have genetic changes in a specific gene the pattern of growth, development, behavior and birth defects are very characteristic. Cornelia de Lange syndrome caused by mutations in the gene NIPBL is an example of this. However, many children with severe developmental disorders do not fall into a specific syndrome diagnosis and, until recently the families and the doctors looking after these children did not know the cause of the problem.

What is DDD?

Deciphering Developmental Disorders (DDD) is a UK and Ireland-wide study funded by the Wellcome Trust and the NIHR. The main purpose of DDD is to identify the cause in children with undiagnosed developmental disorders. Nearly 14,000 families have kindly agreed to take part in DDD and thanks to their participation we have been able to identify a cause in ~40% of cases so far in whom a specific change in an individual gene is responsible for the disease.

What genetic analysis helps?

We now have sequencing technologies that enable all genes in our genome to be analysed in an individual. Using one of these technologies, called whole exome sequencing, each person has about 40,000 different variants. To confidently link one of these genetic variants as the cause of a diagnosis in an affected child requires very careful filtering of the genetic data to ensure both that false diagnoses are not made (i.e. a genetic change is blamed for the disease when in fact it is not responsible) and that real causative changes are not missed. This is particularly problematic in developmental disorders because of the very large number of different possible genetic diseases.

DDG2P

Within DDD we have been curating a database of all the known genetic causes of developmental disorders; DDG2P. There are three important features associated with each causative genetic change;

  • the gene in which it occurs
  • whether one or both copies of the gene have to be changed to cause the disease
  • what the effect of the genetic change is on the gene product
  • We have coded >1400 different genes which are responsible for 1900 different disorders (some genes cause more than one disease). This is now hosted on the Gene2Phenotype at the EBI. This also records the confidence and evidence associated with each of the entries in DDG2P.