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MoBiDiC Prioritization Algorithm, a Free, Accessible, and Efficient Pipeline for Single-Nucleotide Variant Annotation and Prioritization for Next-Generation Sequencing Routine Molecular Diagnosis

Abstract : Interpretation of next-generation sequencing constitutes the main limitation of molecular diagnostics. In diagnosing myopathies and muscular dystrophies, another issue is efficiency in predicting the pathogenicity of variants identified in large genes, especially TTN; current in silico prediction tools show limitations in predicting and ranking the numerous variants of such genes. We propose a variant-prioritization tool, the MoBiDiC prioritization algorithm (MPA). MPA is based on curated interpretation of data on previously reported variants, biological assumptions, and splice and missense predictors, and is used to prioritize all types of single-nucleotide variants. MPA was validated by comparing its sensitivity and specificity to those of dbNSFP database prediction tools, using a data set composed of DYSF, DMD, LMNA, NEB, and TTN variants extracted from expert-reviewed and ExAC databases. MPA obtained the best annotation rates for missense and splice variants. As MPA aggregates the results from several predictors, individual predictor errors are counterweighted, improving the sensitivity and specificity of missense and splice variant predictions. We propose a sequential use of MPA, beginning with the selection of variants with higher scores and followed by, in the absence of candidate pathologic variants, consideration of variants with lower scores. We provide scripts and documentation for free academic use and a validated annotation pipeline scaled for panel and exome sequencing to prioritize single-nucleotide variants from a VCF file.
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https://hal-amu.archives-ouvertes.fr/hal-01991354
Contributor : Valérie Gall <>
Submitted on : Wednesday, January 23, 2019 - 6:00:39 PM
Last modification on : Wednesday, August 19, 2020 - 12:08:17 PM

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Kevin Yauy, David Baux, Henri Pegeot, Charles van Goethem, Charly Mathieu, et al.. MoBiDiC Prioritization Algorithm, a Free, Accessible, and Efficient Pipeline for Single-Nucleotide Variant Annotation and Prioritization for Next-Generation Sequencing Routine Molecular Diagnosis. Journal of Molecular Diagnostics, American Society for Investigative Pathology (ASIP), 2018, 20 (4), pp.465-473. ⟨10.1016/j.jmoldx.2018.03.009⟩. ⟨hal-01991354⟩

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