Targeted variant detection using unaligned RNA-Seq reads

Mutations identified in acute myeloid leukemia patients are useful for prognosis and for selecting targeted therapies. Detection of such mutations using next-generation sequencing data requires a computationally intensive read mapping step followed by several variant calling methods. Targeted mutation identification drastically shifts the usual tradeoff between accuracy and performance by concentrating all computations over a small portion of sequence space. Here, we present km, an efficient approach leveraging k-mer decomposition of reads to identify targeted mutations. Our approach is versatile, as it can detect single-base mutations, several types of insertions and deletions, as well as fusions. We used two independent cohorts (The Cancer Genome Atlas and Leucegene) to show that mutation detection by km is fast, accurate, and mainly limited by sequencing depth. Therefore, km allows the establishment of fast diagnostics from next-generation sequencing data and could be suitable for clinical applications.