MAJIQ-CLIN: A novel tool for the identification of Mendelian disease-causing variants from RNA-Seq data

The current diagnostic rate for patients with suspected Mendelian genetic disorders is only 25 to 58%, even though whole exome sequencing (WES) is part of the standard of care. One reason for the low diagnostic rate is that traditional WES analysis methods struggle to detect RNA splicing aberrations. It is estimated that 15-50% of human pathogenic variants alter splicing, with numerous splice-altering variants being causal for known Mendelian disorders. Developing reliable diagnostic tools to detect, quantify, prioritize, and visualize RNA splicing aberrations from patient RNA sequencing is therefore crucial. We present MAJIQ-CLIN, a method to address this need to augment clinical diagnostic using RNA-Seq and compare it to existing tools. We include the first systematic evaluation of the accuracy of such tools using synthetic data across several aberration types and transcript inclusion levels; we also evaluate accuracy on several datasets of biologically validated solved test cases. We show that MAJIQ-CLIN compares favorably to existing tools in both accuracy and efficiency, then use MAJIQ-CLIN to investigate several unsolved patient cases from the Undiagnosed Diseases Network.