RankVar: machine learning-based variant ranking and reinterpretation for rare genetic diseases.

Abstract

Background: Prior biological knowledge and phenotype information can help identify disease genes from whole genome/exome sequencing studies, but how best to incorporate external knowledge with variant data remains challenging. We developed a machine learning algorithm called RankVar to prioritize causative variants for rare diseases, based on clinical notes and genome/exome sequencing profiles.

Methods: RankVar uses a random forest classifier trained on ~ 1 million variants from the 1000 Genomes Project with spiked-in pathogenic variants. For testing, we compiled sequencing data and phenotype information from several independent datasets: 260 subjects from the Children's Hospital of Philadelphia (CHOP) with positive genetic diagnosis of various Mendelian diseases, 135 subjects from Birth Defects Biorepository (BDB), as well as 356 and 97 subjects with candidate causal variants for autism spectrum disorders from the Simons Simplex Collection (SSC) and the Simons Foundation Powering Autism Research for Knowledge (SPARK), respectively.

Results: RankVar achieves a top 10 variant accuracy of 90.0%, 81.5%, 46.1%, and 76.3% for CHOP, BDB, SSC, and SPARK, respectively, with improved performance over existing approaches. Notably, RankVar successfully identified X-linked and Y-linked disease-causal variants, such as KDM6A (p.N915Kfs5*) and SRY (p.W98X), as the top candidate variants. Moreover, we evaluated RankVar for genomic reinterpretation of 130 unsolved CHOP cases with hearing loss and successfully identified 61 candidate causal variants after manual review.

Conclusions: In summary, RankVar performed favorably relative to existing methods in our evaluation, accommodated different genetic models and X/Y chromosome variants, and may provide a useful framework for prioritizing variants in monogenic or oligogenic diseases. We anticipate that RankVar may aid in primary genetic diagnosis, genome reinterpretation of previously unsolved cases, and the discovery of novel disease genes.