Pathogenic Potential of Genes

The pathogenic potential of a gene is defined as the disease-causing potential of the gene if variants occurred. It could be generally understood as the association between the gene and the genetic disorder or the pathogenic role of the gene in the genetic disorder.

In general, the genetic dependence feature determines the pathogenic potential of genes. However, other factors or pathogenic mechanisms, such as GOF, dominant negative/toxic effect should be considered. For example, the pathogenic effect of PCDH19 involved a mechanism called “cellular interference”, in which a heterogeneous population of mutant and wild-type cells is required for disease to occur, while a homogeneous cell population (either mutant or wild-type) does not lead to disease. From a practical point of view, we propose to evaluate the pathogenic potential of a gene from three profiles with a 10-point scoring, including expression, clinic-genetic, and functional studies.

If a gene presented evidence of pathogenicity in the five clinic-genetic aspects, the stage of gene expression correlated with the onset of phenotype, and the functional alteration explained the pathogenesis, the gene could be evaluated as "pathogenic". If evidence in one or more aspects of the clinic-genetic profile was not available, more evidences from functional studies are required. Therefore, a scoring of 7/10 or higher was set for "pathogenic" in evaluating the pathogenic potential.

If a gene presented evidence of pathogenicity in three of the five clinic-genetic aspects with additional two points in gene expressional and functional profile, or with similar scoring of 5/10, the gene could be evaluated as "possible pathogenic".

If variants in a gene had been identified recurrently in unrelated cases or with significantly high frequency in patient group, but did not have defined inheritance pattern or was associated with apparently incomplete penetrance, the phenotype nature of the gene should be considered as susceptibility, instead of genetic disease, although it was evaluated as pathogenic or possible pathogenic by evidences from other aspects.

Besides evaluation of pathogenic potential, a summary of the pathogenic feature, such as phenotype specificity, pathogenic geno/funo-type or mechanism, severity correlation, and inheritance pattern, are helpful for further evaluation of the pathogenicity of variants in this gene.