Ethical and clinical aspects of genetic analysis in neurodegenerative diseases

Objective. Too conduct a comprehensive analytical review of the limitations of traditional genetic methodologies compared with contemporary high-resolution technologies, such as single-cell and single-nucleus RNA sequencing (sc/snRNA-seq). It will explore in detail the mechanisms underlying the incomplete penetrance of pivotal risk genes, namely LRRK2 and GBA1, and systematically organize data on pathological alterations in specific target cell types, including microglia, astrocytes, oligodendrocytes, and selectively vulnerable neurons. Material and methods. The analysis presented in this paper is grounded in a review of contemporary transcriptomic, genomic, and clinical research. Emphasis is placed on integrating data from genome-wide association studies (GWAS) with single-cell expression atlases, as well as findings from functional studies conducted in model organisms and in cell cultures derived from mutation carriers. Results. The findings indicate that conventional sequencing techniques are inadequate for detecting cell-specific dysfunctions, particularly within rare cell populations. Technologies such as scRNA-seq have demonstrated that the LRRK2 and GBA1 genes exhibit significant expression levels in glial cells, where they are involved in critical processes including immune response modulation, lysosomal function, and cytoskeletal organization. Mutations in LRRK2 reprogram pro-inflammatory microglia and alter astrocyte morphology through hyperphosphorylation of ERM proteins. In contrast, GBA1 deficiency initiates a cascade of lysosomal stress that impacts not only neurons but also astrocytes and oligodendrocytes. The phenomenon of incomplete penetrance is examined, revealing penetrance rates ranging from 10% to 85% that vary by ethnic background and polygenic factors, thereby posing significant challenges for medical and genetic counseling. Conclusions. Neurodegeneration is a systemic process characterized by disruption of glial cell homeostasis, which acts as a pathogenic driver. The advancement of single-cell analytical techniques paves the way for the identification of new therapeutic targets to correct the dysfunction of specific cell populations. The phenomenon of incomplete penetrance necessitates a reevaluation of the strategies used to predict and apply polygenic risk assessments in clinical practice.