A tissue-aware machine learning framework enhances the mechanistic understanding and genetic diagnosis of Mendelian and rare diseases

ABSTRACT Genetic studies of Mendelian and rare diseases face the critical challenges of identifying pathogenic gene variants and their modes-of-action. Previous efforts rarely utilized the tissue-selective manifestation of these diseases for their elucidation. Here we introduce an interpretable machine learning (ML) platform that utilizes heterogeneous and large-scale tissue-aware datasets of human genes, and rigorously, concurrently and quantitatively assesses hundreds of candidate mechanisms per disease. The resulting tissue-aware ML platform is applicable in gene-specific, tissue-specific, or patient-specific modes. Application of the platform to selected Mendelian disease genes pinpointed mechanisms that lead to tissue-specific disease manifestation. When applied jointly to diseases that manifest in the same tissue, the models revealed common known and previously underappreciated factors that underlie tissue-selective disease manifestation. Lastly, we harnessed our ML platform toward genetic diagnosis of tissue-selective rare diseases. Patient-specific models of candidate disease-causing genes from 50 patients successfully prioritized the pathogenic gene in 86% of the cases, implying that the tissue-selectivity of rare diseases aids in filtering out unlikely candidate genes. Thus, interpretable tissue-aware ML models can boost mechanistic understanding and genetic diagnosis of tissue-selective heritable diseases. A webserver supporting gene prioritization is available at https://netbio.bgu.ac.il/trace/ .