The Deciphering Developmental Disorders (DDD) study

BACKGROUND TO THE STUDY One of the main frustrations facing paediatric neurologists, community paediatricians, and clinical geneticists in everyday practice is the poor success rate in making accurate diagnoses for children with severe or profound neurological disability. Accurate diagnosis is the cornerstone of good medical care. However, the chance of achieving a genetic diagnosis for a child with severe developmental delay is low where no diagnosis is apparent after routine investigation – yet the majority of children with developmental disorders fall into this category. Although individually rare, collectively these conditions represent a significant burden for individuals, families, and health services. There has been a growing appreciation in recent years of the importance of genetic disorders in childhood neurodisability, although in many cases the location and nature of the causal mutation is unknown. In clinical practice, a family history of other similarly affected individuals is a strong pointer to a genetic aetiology, but the converse does not necessarily hold and the concept that de novo dominant mutations may cause apparently sporadic disorders is gaining acceptance. If a de novo mutation severely impairs development such that the affected individual does not reproduce, the genetic basis of their condition may remain unrecognized. Speculatively, such events may explain some cases of severe cerebral palsy or severe epileptic encephalopathy as well as severe intellectual disability. In addition, there are many undiagnosed recessively inherited neurodevelopmental disorders collectively responsible for a substantial proportion of the excess morbidity and mortality amongst infants born to consanguineous parents. Genomic microarray analysis has proven to be valuable for improving rates of diagnosis amongst children with developmental delay ⁄ intellectual disability caused by large structural variants (such as deletions and duplications of >50kb). For smaller mutations, the revolution in ‘next generation’ DNA sequencing technologies is now enabling genomic analysis on an unprecedented scale. Massively parallel sequencing enables the rapid, systematic identification of variants on a large scale, either across the whole genome or targeted at functional coding regions (the exome). This has accelerated the pace of gene discovery and disease diagnosis on a molecular level and may substantially improve the diagnosis of children with developmental disorders.