GENETIC MODIFIERS OF THE COURSE OF DISEASES: FROM IDENTIFICATION TO THERAPEUTIC TARGETS

Abstract

The variability of the clinical course of diseases is increasingly rarely explained only by the presence of a causal mutation or the belonging of a case to a specific nosology. The severity of symptoms, age of onset, rate of progression, and response to treatment are influenced by genetic modifiers - rare coding variants, regulatory non-coding changes, copy rearrangements, mitochondrial background, and polygenic combinations.

The aim of the work is to systematize modern approaches to the identification of such modifiers and to show how they become therapeutic targets, as well as to assess the Russian context of the introduction of modifier-based strategies. The study used an analytical review of translational approaches and a simulated scenario expert survey for the Russian Federation based on a sample of 80 respondents.

It has been established that the greatest practical demand for accounting for genetic modifiers in the Russian Federation is related to oncology, neurogenetics and orphan hereditary diseases. Rare coding and regulatory variants, as well as copy rearrangements and somatic clonal events, are indicated as the most clinically significant classes.

 Among the key barriers are the high cost of sequencing and interpretation, the lack of unified bioinformatic circuits, limited national reference databases, and uneven infrastructure between regions. The respondents consider stratification of patients for the choice of targeted therapy and RNA-based approaches to be the most mature therapeutic routes, while direct genome editing is still perceived as a promising but less affordable solution.

It is concluded that the transition from identification of modifiers to drug targets requires the integration of human genetics, multi-layered omics data, functional validation and an organized clinical network. Standardization of interpretation, expansion of biobanks, and building a route from a genetic finding to clinical action are fundamentally important for the Russian Federation.