Sharing of genetic data empowers discovery of new disorders in children

Four new genetic disorders identified

The team behind the Deciphering Developmental Disorders (DDD) Study, one of the world’s largest nationwide rare disease genome-wide sequencing initiatives, have developed a novel computational approach to identify genetic variants that cause disease in young children. This approach is only made possible by contrasting the DNA of children with severe developmental disorders of unknown genetic cause, with the DNA from individuals without overt developmental disorders. These research participants were drawn from around the globe.

There are over 1,000 different genetic causes of developmental disorders that have already been identified, but these only account for about one third of all children with such disorders. Most individual developmental disorders are so rare that they confound efforts to uncover their causes, hence the importance of taking a nationwide approach.

In the study, published in Nature Genetics, the DDD team analysed samples from more than 4,000 families from across the UK and Republic of Ireland with at least one child affected by a developmental disorder and applied a computational strategy to identify clusters of affected children that had similar clinical characteristics and shared damaging genetic variants in the same gene. Comparing the variants observed in these genes in the affected children with genetic variation observed in over 60,000 research participants – who have agreed to share their genetic data to support medical research – allowed the team to identify four previously uncharacterised genetic disorders.

The power of the study is built on the contribution of many thousands of people who have agreed to share genetic data to support medical research, and the work of the Exome Aggregation consortium (ExAC) in bringing those data together and making them available widely.

“With the contribution of many thousands of people to medical research, we have the power to uncover mutations behind some devastating conditions. Their altruism can unlock the secrets in our genomes, providing answers to families desperate to understand their child’s condition and enabling those families to access support and engage in further studies researching possible therapeutic strategies.”

Dr Matthew Hurles Project leader at the Wellcome Trust Sanger Institute

The DDD team focused on genetic disorders where a child inherits a damaged copy of a gene from both parents, neither of whom have the disorder because they also carry an undamaged ‘back-up’ copy of the gene. Defining genetic variants that cause such rare disorders has previously most often relied on studies of extensive family trees, where several people are affected with the same disorder, or of studies of unrelated individuals sharing the same, very distinctive, disorder. For many developmental disorders, these requirements are not met.

The team screened genes encoding over 18,000 proteins in the families’ genomes, searching for variants that might prevent each protein from working, and uncovered 74 genes in which mutations might play a role. For four of these genes, comparisons with the ExAC dataset revealed that these damaging variants were greatly enriched in the affected children compared to individuals without developmental disorders.

The children’s conditions were systematically clinically assessed to objectively characterise the disorder. This systematic assessment was essential for large-scale computational analysis.

“It is only by combining large datasets with computational analysis and systematic description of the clinical conditions that we can identify these causative variants. The distinctiveness of both genotype and phenotype was used to discover rare recessive disorders. The genotype score was especially useful for those with less specific clinical presentations. The combined score identified ultra-rare but clinically-recognisable syndromes.

“This doesn’t bring new treatments but Without knowing the underlying genetic cause, we don’t even know where to start that search. A genetic diagnosis helps families in their understanding of their child’s disorder, can help them to access other support and allow them to engage in further studies researching possible therapeutic strategies.”

Professor David FitzPatrick from the MRC Human Genetics Unit at the University of Edinburgh

The damaging variants in children with developmental disorders affected genes involved in brain development, configuring of the heart and other organs in early embryonic development, and bone growth. For each of the four new disorders, additional support came from observing that mice having a mutation in the equivalent gene shared many characteristics that resembled the human condition.

“New strategies for discovering the genetic causes of rare disease are desperately needed. This study shows the value of clever analysis methods, together with genetic data from populations around the world from the ExAC project, to find answers for rare disease families.”

Dr Daniel MacArthur, Assistant Professor at Harvard Medical School and the coordinator of the ExAC project, who was not involved in the study.

More information


The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). Please see the paper for further funding details.

Participating Centres

  • Wellcome Trust Sanger Institute, Cambridge, UK
  • MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Edinburgh, Scotland
  • Sheffield Regional Genetics Services, Sheffield Children’s NHS Trust, Sheffield, UK
  • Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Leeds, UK
  • North West Thames Regional Genetics Service, London North West Healthcare NHS Trust, London, UK
  • West Midlands Regional Genetics Service, Birmingham Women’s NHS Foundation Trust, Birmingham, UK
  • South East Thames Regional Genetics Centre, Guy’s and St Thomas’ NHS Foundation Trust, London, UK
  • Wessex Clinical Genetics Service, University Hospital Southampton, Princess Anne Hospital, and Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury District Hospital, and Faculty of Medicine, University of Southampton, Southampton, UK
  • Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA, USA
  • Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Institute of Human Genetics, International Centre for Life, Newcastle upon Tyne, UK
  • West of Scotland Regional Genetics Service, NHS Greater Glasgow and Clyde, Institute Of Medical Genetics, Yorkhill Hospital, Glasgow, UK
  • North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street Hospital, London, UK
  • Peninsula Clinical Genetics Service, Royal Devon and Exeter NHS Foundation Trust, Clinical Genetics Department, Royal Devon & Exeter Hospital (Heavitree), Exeter, UK
  • Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK
  • Deciphering Developmental Disorders Project

DDD membership described in Supplementary Note


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Selected websites

  • The Health Innovation Challenge Fund

    The Health Innovation Challenge Fund is a parallel funding partnership between the Wellcome Trust and the Department of Health to stimulate the creation of innovative healthcare products, technologies and interventions and to facilitate their development for the benefit of patients in the NHS and beyond.

  • The Department of Health (DH)

    The Department of Health (DH) helps people to live better for longer. The Department leads, shapes and funds health and care in England, making sure people have the support, care and treatment they need, with the compassion, respect and dignity they deserve. The Department funds health research and encourages the use of new technologies because it’s important to the development of new, more effective treatments for NHS patients. Innovation is needed so that decisions about health and care are based on the best and latest evidence.

  • Deciphering Developmental Disorders (DDD UK)

    The aim of the Deciphering Developmental Disorders study is to advance clinical genetic practice for children with developmental disorders by the systematic application of the latest microarray and sequencing methods while addressing the new ethical challenges raised.

  • The Wellcome Trust Sanger Institute

    The Wellcome Trust Sanger Institute is one of the world’s leading genome centres. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease.