Using reported pathogenic variants to identify therapeutic opportunities for genetic diseases

Area of Science:

• Genetics
• Pharmacology
• Bioinformatics

Background:

• Accurate classification of pathogenic genetic variants (loss-of-function vs. gain-of-function) is crucial for developing effective drug strategies for genetic diseases.
• For many genes, the precise effect of pathogenic variants remains undetermined, hindering targeted therapeutic development.

Purpose of the Study:

• To develop a novel computational approach for inferring the direction of effect (loss- or gain-of-function) of pathogenic variants.
• To classify Mendelian disease genes based on variant effect direction to inform drug development.

Main Methods:

• Leveraged the increasing number of reported pathogenic variants in genetic databases.
• Quantified the ratio of reported missense pathogenic variants to loss-of-function variants for gene classification.

Main Results:

• Demonstrated that the ratio of missense to loss-of-function variants is diagnostic for many dominant Mendelian disease genes.
• Identified a subset of genes primarily causing disease through gain-of-function or hypermorphic mechanisms.

Conclusions:

• Proposed a method to classify pathogenic variants, aiding in understanding disease mechanisms.
• Identified 16 specific genes as promising candidates for drug development strategies involving direct inhibition.