An Integrated Taxonomy for Monogenic Inflammatory Bowel Disease

Area of Science:

• Genetics
• Immunology
• Gastroenterology

Background:

• Monogenic forms of inflammatory bowel disease (IBD) highlight the critical roles of specific genes in maintaining immune tolerance and gut homeostasis.
• Understanding these genetic underpinnings is crucial for developing targeted diagnostics and therapies.

Purpose of the Study:

• To develop a comprehensive taxonomy model for monogenic IBD genes.
• To classify genes based on syndromic features, treatment response, and multi-omics data.
• To explore genotype-phenotype associations and cellular networks in monogenic IBD.

Main Methods:

• A taxonomy model was built by assessing 165 disorders and prioritizing genes based on IBD penetrance.
• Multi-omics datasets, including bulk and single-cell RNA sequencing and proteomes, were integrated.
• Genes were classified using overlapping syndromic features, response to hematopoietic stem cell transplantation, and expression profiles across diverse cell types.

Main Results:

• A quantitative taxonomy was established for 102 monogenic IBD genes, defining their cellular landscape.
• Distinct cellular networks and expression profiles in understudied cell types (e.g., CD8+ T cells, neutrophils) were identified.
• Genotype-phenotype associations, including perianal disease and defective antimicrobial activity, were defined, revealing overlaps with polygenic IBD.

Conclusions:

• The developed taxonomy integrates genetic, clinical, and multi-omic data, forming a foundation for genomic diagnostics.
• It provides testable hypotheses for understanding disease mechanisms and predicting treatment responses in monogenic IBD.
• This approach aids in elucidating the complex interplay of genes, cells, and pathways in IBD pathogenesis.