LIRICAL’s Genotype Score

We can estimate the pathogenicity of a variant on the basis of a computational pathogenicity score that ranges from 0 (predicted benign) to 1 (maximum pathogenicity prediction). LIRICAL uses the pathogenicity score prediction of Exomiser. Our model depends on the assumed mode of inheritance of the disease, and provides an estimate likelihood ratio for the observed genotype. For example, we expect two pathogenic alleles in an autosomal recessive disease and one in an autosomal dominant disease. Our model takes into account the expected frequency of seeing predicted pathogenic variants in the population. Genes known to carry few common functional variants in healthy individuals may be judged more likely to cause certain kinds of disease than genes known to carry many such variants (Petrovski et al., 2013).

LIRICAL’s model provides an integrated score for each gene that assesses the observed genotype, comparing its probability given that a disease associated with the gene is present in the proband vs. the probability that the genotype is unrelated to the clinical manifestations observed in the proband. See the manuscript for algorithmic details.