Semantic prioritization of novel causative genomic variants

Author summary We address the problem of how to distinguish which of the many thousands of DNA sequence variants carried by an individual with a rare disease is responsible for the disease phenotypes. This can help clinicians arrive at a diagnosis, but also can be instrumental in improving our understanding of the pathobiology of the disease. Many methods are currently available to help with the problem of determining causative variant, using information about evolutionary conservation and prediction of the functional consequences of the sequence variant. We have developed a novel algorithm (PVP) which augments existing strategies by using the similarity of the patients phenotype to known phenotype-genotype data in human and model organism databases to further rank potential candidate genes. In a retrospective study, we apply PVP to the interpretation of whole exome sequencing data in patients suffering from congenital hypothyroidism, and find that PVP accurately identifies causative variants in whole exome and whole genome sequencing datasets and provides a powerful resource for the discovery of causal variants.