Solving the Unsolved (STU)


Progress toward the discovery of the genetic basis of every rare disease has been substantial over the past several years; approximately 200 new disease genes are discovered per year using primarily an exome sequencing approach. However, there remains a non-trivial number of well-known rare conditions for which, despite efforts by multiple groups using whole exome sequencing (WES), and in some cases, whole genome sequencing (WGS), the causal genetic mechanisms remain elusive. The reasons for why such discovery efforts fail are myriad and likely include both technical limitations (e.g., annotation errors, missed coding and non-coding variation, structural variation, etc.) and complex mechanisms (extreme locus heterogeneity, tissue-specific somatic mosaicism, unusual modes of inheritance, intra-familial allelic or locus heterogeneity, causal synonymous variants, epigenetics etc.). Approaches to overcome these barriers to gene discovery are currently limited.


The ‘Solving the Unsolved’ Task Force will bring together world experts in each of the areas suspected to contribute to the rare diseases and patients/families that remain unsolved following WES analysis:

  • Tissue-specific mosaicism
  • Splicing mutations
  • Other regulatory mutations – promoter, enhancers
  • Chromosome rearrangements and repeat expansions
  • Imprinting
  • Gene-environment interaction

The mandate of the Solving the Unsolved Task Force is to:

  • Develop a state-of-play document, including a comprehensive list of recognizable disorders that are currently unsolved with existing approaches
  • Organize a workshop to present cutting edge research and innovative approaches in the areas of focus
  • Develop an asset map, and identify gaps and missing tools
  • Develop a set of recommendations to advance these approaches
  • Publish a review paper on the scope of the problem and strategies to address the challenges

This Task Force aims to ultimately enable the disease etiology for every patient be understood.

Members (14)

  • Kym Boycott – Children’s Hospital of Eastern Ontario Research Institute, Canada (Chair)
  • Gareth Baynam – Western Australian Department of Health, Australia
  • Leslie Biesecker – National Human Genome Research Institute Home at NIH, USA
  • Sally Dunwoodie – Victor Chang Cardiac Research Institute, Australia
  • Richard Gibbs – Baylor College of Medicines, USA
  • Taila Hartley – Children’s Hospital of Eastern Ontario Research Institute, Canada
  • Matthew Hurles – Wellcome Sanger Institute & DDD, UK
  • Nebojsa Jojic – Microsoft, USA
  • Timo Lassmann – Telethon Kids Institute, Australia
  • Daniel MacArthur – Broad Institute, USA
  • Deborah Mackay – University of Southampton, UK
  • Olaf Riess – Institut für Medizinische Genetik und Angwandte Genomik, Germany
  • Karen Temple – University of Southampton, UK
  • Axel Visel – Lawrence Berkeley National Lab, USA


Comments and suggestions

To submit your comments and suggestions on this Task Force, please contact us by completing this form.