Gene-disease association: pathogenic potential/pathogenic feature assessment

Abstract Determining gene-disease associationsis an essential task but a major challenge of genetic studies. It is also the precondition for evaluating the pathogenicity of variants. Considering what determines the gene-disease association and which clinical-genetic features reflect the gene-disease association, we proposed a pathogenic potential and pathogenic feature assessment (PPA) system to evaluate the gene-disease association. In addition to case/variant number, PPA evaluates the clinical-genetics evidence from phenotypic specificity, inheritance pattern, genotype-phenotype correlation, and submolecular implication of variants, which represent the pathogenic feature of the gene. PPA refers to experimental evidence directly related to gene-disease associations, including gene expression and knockout, and the functional consequencesof variants. We collected data on all potentially functioning genes (19,711) and assessed those with available clinical data, and 3,623 genes were evaluated as “pathogenic”/“possibly pathogenic”. The pathogenic features of genes were summarized, providing critical information for evaluating the pathogenicity of variants. PPA considers the genetic dependent feature that differs in each gene and determines the pathogenicity of genes and evaluates whether (pathogenic potential) and how (pathogenic feature) a gene is associated with a disease and avoidsbias associated with special genotype or inheritance, potentially being a framework in future studies in defining the gene-disease association.