Genetically transitional disease: conceptual understanding and applicability to rheumatic disease

Area of Science:

• Genomic medicine
• Rheumatic diseases
• Genetic susceptibility

Background:

• Rheumatic diseases are linked to numerous genetic variants, falling between monogenic and common susceptibility alleles.
• Low-frequency and low-penetrance variants in autoinflammatory disease genes increase systemic inflammation risk.
• Hundreds of HLA and non-HLA variants are modest- to moderate-risk alleles in autoimmune diseases.

Approach:

• Applying the novel concept of genetically transitional disease (GTD) to rheumatic conditions.
• Analyzing genetic variants in the 'grey zone' between large-effect monogenic variants and small-effect common alleles.
• Reclassifying autoimmune and autoinflammatory diseases as GTDs.

Key Points:

• Genetically transitional disease (GTD) framework: gene mutation is necessary but not sufficient.
• GTD concept applicable to rheumatic diseases, including autoimmune and autoinflammatory conditions.
• Identifies a 'grey zone' of genetic variants influencing disease risk.

Conclusions:

• Reclassifying rheumatic diseases as GTDs can enhance genetic testing interpretation and diagnostic yield.
• The GTD concept offers a novel approach for genetic counseling, therapy selection, and research in human genetic diseases.
• This framework has potential applications across a wide range of human diseases beyond rheumatology.