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A phenotype centric benchmark of variant prioritisation tools.
Denise Anderson1, Timo Lassmann1
1Telethon Kids Institute, The University of Western Australia, Subiaco, WA 6008 Australia.
NPJ Genomic Medicine
|February 10, 2018
Summary
Variant prioritization tools are crucial for diagnosing Mendelian diseases using next-generation sequencing. Their performance varies significantly by disease phenotype, necessitating further development for accurate etiological variant discovery.
Area of Science:
- Genomics and Bioinformatics
- Clinical Diagnostics
- Genetic Disease Research
Background:
- Next-generation sequencing (NGS) is a standard clinical diagnostic tool.
- Identifying etiological variants in Mendelian diseases is challenging due to numerous benign variants.
- Variant prioritization tools analyze variant conservation and functional consequences.
Purpose of the Study:
- To investigate if the performance of variant prioritization tools varies by disease phenotype.
- To create benchmark datasets for evaluating tools across different disease contexts.
- To identify top-performing tools and analytical approaches for variant prioritization.
Main Methods:
- Development of benchmark datasets for variants associated with diverse disease phenotypes.
- Evaluation of the performance of 24 different variant prioritization tools.
- Comparative analysis of tool performance across various disease contexts.
Main Results:
- Tool performance is highly variable and significantly differs based on disease phenotype.
- All tested tools face challenges in distinguishing causative variants from benign ones.
- Five tools (FATHMM, M-CAP, MetaLR, MetaSVM, VEST3) demonstrated superior performance.
Conclusions:
- The effectiveness of variant prioritization tools is context-dependent, varying by disease.
- Further development is needed to improve the accuracy of etiological variant identification.
- Tools perform better for well-studied genetic diseases compared to rare diseases.
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