The Deciphering Developmental Disorders (DDD) study

Abstract

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.1 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.2 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).3 For smaller mutations, the revolution in 'next generation' DNA sequencing technologies is now enabling genomic analysis on an unprecedented scale.4 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 level5 and may substantially improve the diagnosis of children with developmental disorders.6 The Deciphering Developmental Disorders (DDD) study is an ambitious project, combining the clinical expertise of all 23 UK NHS Regional Genetics Services with the research and bioinformatics expertise of the Wellcome Trust Sanger Institute, to undertake systematic phenotyping and detailed genomic analysis for 12 000 children with severe undiagnosed developmental disorders (Table I). This National Institute for Health Research Portfolio project is funded by the Health Innovation Challenge Fund and the Wellcome Trust Sanger Institute and began recruiting patients in April 2011 (see http://www.ddduk.org). The study will recruit 'trios', i.e. a child and both parents, and use multiple complementary genome-wide approaches – high resolution array-comparative genomic hybridization (aCGH), common variant (SNP) genotyping, and whole exome sequencing – to facilitate identification of de novo variants in the child and improve the chances of identifying relevant recessive mutations. In order to maximize the investment in detailed genomic analysis, the study uses the recently developed Human Phenotype Ontology (HPO)7 which enables comprehensive phenotypic description. The controlled vocabulary in HPO will facilitate association analysis between phenotypes and genomic variants, as well as links to other genetic studies and work in model organisms. The use of whole genome technologies in research and their translation to clinical practice raises numerous social, legal, and ethical issues, such as how to deal with findings that are incidental to the research question or clinical diagnosis.8 Embedded within the DDD project as a core activity is a programme of empirical ethical and social science research, which aims to develop strategies to gain maximum benefit from these new technologies whilst minimizing potential harm. An accurate genetic diagnosis is important for prognosis and management of affected children, and for counselling parents about the likely risk of recurrence. DDD is a translational project and it is hoped that, through the study, several thousand families will receive a genetic diagnosis for their child's developmental disorder. Furthermore, the study will facilitate better design of diagnostic assays and create an important knowledge-base for improved diagnosis of genomic disorders in the future. Analysis of OMIM statistics in April 2011 shows that entries with a phenotype description for which the molecular basis was known totalled 2993. Of an estimated 21 000 genes in