An AI-based approach driven by genotypes and phenotypes to uplift the diagnostic yield of genetic diseases

Abstract Identifying disease-causing variants in Rare Disease patients’ genome is a challenging problem. To accomplish this task, we describe a machine learning framework, that we called “Suggested Diagnosis”, whose aim is to prioritize genetic variants in an exome/genome based on the probability of being disease-causing. To do so, our method leverages standard guidelines for germline variant interpretation as defined by the American College of Human Genomics (ACMG) and the Association for Molecular Pathology (AMP), inheritance information, phenotypic similarity, and variant quality. Starting from (1) the VCF file containing proband’s variants, (2) the list of proband’s phenotypes encoded in Human Phenotype Ontology terms, and optionally (3) the information about family members (if available), the “Suggested Diagnosis” ranks all the variants according to their machine learning prediction. This method significantly reduces the number of variants that need to be evaluated by geneticists by pinpointing causative variants in the very first positions of the prioritized list. Most importantly, our approach proved to be among the top performers within the CAGI6 Rare Genome Project Challenge, where it was able to rank the true causative variant among the first positions and, uniquely among all the challenge participants, increased the diagnostic yield of 12.5% by solving 2 undiagnosed cases.