Efficient reinterpretation of rare disease cases using Exomiser
Abstract 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...
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| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-12-01
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| Series: | npj Genomic Medicine |
| Online Access: | https://doi.org/10.1038/s41525-024-00456-2 |
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| Summary: | Abstract 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. |
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| ISSN: | 2056-7944 |