Efficient reinterpretation of rare disease cases using Exomiser
Whole genome sequencing has transformed rare disease research; however, 50-80% of rare disease patients remain undiagnosed after such testing. Regular reanalysis can identify new diagnoses, especially in newly discovered disease-gene associations, but efficient tools are required to support clinical interpretation. Exomiser, a phenotype-driven variant prioritisation tool, fulfils this role; within the 100,000 Genomes Project (100kGP), diagnoses were identified after reanalysis in 463 (2%) of 24,015 unsolved patients after previous analysis for variants in known disease genes. However, extensive manual interpretation was required. This led us to develop a reanalysis strategy to efficiently reveal candidates from recent disease gene discoveries or newly designated pathogenic/likely pathogenic variants. Optimal settings to highlight new candidates from Exomiser reanalysis were identified with high recall (82%) and precision (88%) when including Exomiser's automated ACMG/AMP classifier, which correctly converted 92% of variants from unknown significance to pathogenic/likely pathogenic. In conclusion, Exomiser efficiently reinterprets previously unsolved cases.
Authors
- Chris Mungall (ORCID: https://orcid.org/0000-0002-6601-2165)
- Damian Smedley (ORCID: https://orcid.org/0000-0002-5836-9850)
- Nomi L. Harris (ORCID: https://orcid.org/0000-0001-6315-3707)
- Peter N. Robinson (ORCID: https://orcid.org/0000-0002-0736-9199)
- Melissa Haendel (ORCID: https://orcid.org/0000-0001-9114-8737)
- Letizia Vestito (ORCID: https://orcid.org/0000-0003-0008-936X)
- Julius O.B. Jacobsen (ORCID: https://orcid.org/0000-0002-3265-1591)
- Susan Walker
- Valentina Cipriani (ORCID: https://orcid.org/0000-0002-0839-9955)
Institutions
- Department of Health and Social Care (GB)
- Lawrence Berkeley National Laboratory (US)
- Queen Mary University of London (GB)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Genomics England (GB)
- William Harvey Research Institute (GB)
- University of Colorado Anschutz Medical Campus (US)
Publication Details
- Journal
- npj Genomic Medicine
- Published
- 2024-12-18
- DOI
- https://doi.org/10.1038/s41525-024-00456-2
- Citations
- 16
- Primary Topic
- Genomics and Rare Diseases
- Type
- article
- Field-Weighted Citation Impact
- 8.81
Funders
- Foundation for the National Institutes of Health
- Wellcome Trust
- Cancer Research UK
- National Institute for Health and Care Research
- Department of Health and Social Care
- National Institutes of Health
- Medical Research Council
- National Institute of Child Health and Human Development