Genetically Transitional Disease and the Road to Personalized Medicine

Area of Science:

• Genomic Medicine
• Medical Genetics
• Disease Classification

Background:

• Traditional disease classification relies on monogenic (single gene) or polygenic (multiple genes) models.
• Variants of uncertain significance (VUS) present challenges in clinical interpretation and are often overlooked.
• Mendelian disorders involve high-penetrance variants, while polygenic disorders involve complex genetic interactions.

Purpose of the Study:

• Introduce the concept of Genetically Transitional Disease (GTD) to bridge the gap between monogenic and polygenic diseases.
• Propose a framework for classifying and interpreting VUS within the GTD model.
• Highlight the impact of low-to-moderate effect gene variants influenced by genetic background.

Main Methods:

• Conceptual framework development for GTD.
• Review of existing guidelines for variant classification (e.g., ACMG).
• Analysis of the role of VUS in disease pathogenesis.

Main Results:

• GTD accommodates variants that are necessary but not sufficient for disease development.
• VUS can be provisionally classified as GTD-associated variants for improved interpretation.
• The GTD concept addresses the 'gray zone' between Mendelian and polygenic diseases.

Conclusions:

• The GTD concept offers a novel approach to understanding genetic diseases with complex inheritance patterns.
• Implementing GTD can enhance the clinical utility of VUS, impacting patient care and research.
• Focusing on individual variability in disease response is crucial for advancing genomic medicine.