ArticleLancet (London, England)2015
Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data.
Article in Lancet (London, England), 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 437 papers, 3 of them syntheses that pooled it.
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Who cites it
437 citing papers in PubMed, 3 syntheses or guidelines pooled it, 787 citations in OpenAlex.
- Review of Recurrently Mutated Genes in Craniosynostosis Supports Expansion of Diagnostic Gene Panels.Genes · 2023Pooled it
- Identifying the genetic causes of developmental disorders and intellectual disability in Africa: a systematic literature review.Frontiers in genetics · 2023Pooled it
- Correlation between Phenotype and Genotype in CTNNB1 Syndrome: A Systematic Review of the Literature.International journal of molecular sciences · 2022Pooled it
- A nationwide prospective randomized trial for diagnosing developmental disorders demonstrates genome sequencing outperforms standard of care.Genome medicine · 2026Trial
- Genome sequencing for the diagnosis of intellectual disability as a paradigm for rare diseases in the French healthcare setting: the prospective DEFIDIAG study.Genome medicine · 2025Trial
- Disruption of major Ptchd1 isoforms causes autistic traits in social behavior and communication.Molecular psychiatry · 2026Article
- Detecting pathogenic structural variation in families with undiagnosed rare disease in a national genome project.European journal of human genetics : EJHG · 2026Article
- Molecular heterogeneity and diagnostic performance of phenotype-driven multigene panel testing in patients with marfanoid habitus.Journal of applied genetics · 2026Article
- Genome sequencing reveals high diagnostic yield in children with severe sporadic developmental language disorder.European journal of human genetics : EJHG · 2026Article
- Best practice recommendations for bioinformatics approaches applied to high-throughput sequencing for rare disease and cancer diagnosis within the UK National Health Service.Journal of medical genetics · 2026Article
- A functional role for Septin-2 in the maintenance of the axon initial segment and in human cognitive development.Brain : a journal of neurology · 2026Article
- 'Everyday genetics' in the Mass Observation Project: insights on genetics from people writing for an archive of everyday life in Britain.European journal of human genetics : EJHG · 2026Article
- Article
- Blood-based RNA-Seq of 5412 individuals with rare disease identifies new candidate diagnoses in the National Genomic Research Library.medRxiv : the preprint server for health sciences · 2026Article
- Functional signatures of de novo GABBR1 and GABBR2 variants associated with neurodevelopmental disorders.NPJ genomic medicine · 2026Article
- Leveraging protein language models and a scoring function for indel characterization and transfer learning.Patterns (New York, N.Y.) · 2026Article
- Assessment of In-Frame Indel Variants in an Unsolved Cohort of Inherited Retinal Diseases Using Machine Learning.Human mutation · 2026Article
- Rare variants ofFrontiers in cell and developmental biology · 2026Article
- Joint profiling of cell morphology and gene expression during in vitro neurodevelopment.eLife · 2025Article
- Proteome-wide model for human disease genetics.Nature genetics · 2025Article
377 more citing papers are in PubMed but not listed here.
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Authors and funding
33 authors at 4 institutions in 2 countries.
Funding
Abstract
backgroundHuman 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.
methodsThe 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.
findingsAround 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.
interpretationImplementation 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.
fundingHealth Innovation Challenge Fund, a parallel funding partnership between the Wellcome Trust and the UK Department of Health.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.