title: Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data.
abstract: BACKGROUND
  Human genome sequencing has transformed our understanding of genomic variation and its relevance to health and disease, and is now starting to enter clinical practice for the diagnosis of rare diseases. The question of whether and how some categories of genomic findings should be shared with individual research participants is currently a topic of international debate, and development of robust analytical workflows to identify and communicate clinically relevant variants is paramount.
  
  
  METHODS
  The Deciphering Developmental Disorders (DDD) study has developed a UK-wide patient recruitment network involving over 180 clinicians across all 24 regional genetics services, and has performed genome-wide microarray and whole exome sequencing on children with undiagnosed developmental disorders and their parents. After data analysis, pertinent genomic variants were returned to individual research participants via their local clinical genetics team.
  
  
  RESULTS
  Around 80,000 genomic variants were identified from exome sequencing and microarray analysis in each individual, of which on average 400 were rare and predicted to be protein altering. By focusing only on de novo and segregating variants in known developmental disorder genes, we achieved a diagnostic yield of 27% among 1133 previously investigated yet undiagnosed children with developmental disorders, whilst minimising incidental findings. In families with developmentally normal parents, whole exome sequencing of the child and both parents resulted in a 10-fold reduction in the number of potential causal variants that needed clinical evaluation compared to sequencing only the child. Most diagnostic variants identified in known genes were novel and not present in current databases of known disease variation.
  
  
  CONCLUSIONS
  Implementation of a robust translational genomics workflow is achievable within a large-scale rare disease research study to allow feedback of potentially diagnostic findings to clinicians and research participants. Systematic recording of relevant clinical data, curation of a gene-phenotype knowledge base, and development of clinical decision support software are needed in addition to automated exclusion of almost all variants, which is crucial for scalable prioritisation and review of possible diagnostic variants. However, the resource requirements of development and maintenance of a clinical reporting system within a research setting are substantial.
  
  
  BACKGROUND
  Health Innovation Challenge Fund, a parallel funding partnership between the Wellcome Trust and the UK Department of Health.
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK. Electronic address: caroline.wright@sanger.ac.uk.
authors.forename: Caroline F
authors.initials: CF
authors.lastname: Wright
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
authors.forename: Tomas W
authors.initials: TW
authors.lastname: Fitzgerald
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
authors.forename: Wendy D
authors.initials: WD
authors.lastname: Jones
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Clayton
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
authors.forename: Jeremy F
authors.initials: JF
authors.lastname: McRae
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
authors.forename: Margriet
authors.initials: M
authors.lastname: van Kogelenberg
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: King
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
authors.forename: Kirsty
authors.initials: K
authors.lastname: Ambridge
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Barrett
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
authors.forename: Tanya
authors.initials: T
authors.lastname: Bayzetinova
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
authors.forename: A Paul
authors.initials: AP
authors.lastname: Bevan
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
authors.forename: Eugene
authors.initials: E
authors.lastname: Bragin
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
authors.forename: Eleni A
authors.initials: EA
authors.lastname: Chatzimichali
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Gribble
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Jones
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
authors.forename: Netravathi
authors.initials: N
authors.lastname: Krishnappa
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Mason
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
authors.forename: Ray
authors.initials: R
authors.lastname: Miller
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK; Institute of Psychiatry, King's College London, London, UK; Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Katherine I
authors.initials: KI
authors.lastname: Morley
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
authors.forename: Vijaya
authors.initials: V
authors.lastname: Parthiban
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
authors.forename: Elena
authors.initials: E
authors.lastname: Prigmore
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
authors.forename: Diana
authors.initials: D
authors.lastname: Rajan
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Sifrim
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
authors.forename: G Jawahar
authors.initials: GJ
authors.lastname: Swaminathan
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
authors.forename: Adrian R
authors.initials: AR
authors.lastname: Tivey
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Middleton
authors.affiliation: The Ethox Centre, Nuffield Department of Population Health University of Oxford, Old Road Campus, Oxford, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Parker
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Carter
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Barrett
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Hurles
authors.affiliation: MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, WGH, Edinburgh, UK.
authors.forename: David R
authors.initials: DR
authors.lastname: FitzPatrick
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK; Cambridge University Hospitals Foundation Trust, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Helen V
authors.initials: HV
authors.lastname: Firth
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000175:diagnosis* / Q000235:genetics; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D015894:Genome, Human / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D006579:Heterozygote; D006801:Humans; D033162:Incidental Findings; D007223:Infant; D007231:Infant, Newborn; D033181:Information Dissemination; D008297:Male; D010641:Phenotype; D013048:Specimen Handling