Immune system

Germline

Disease

Biology

Gene

Phenotype

Pathology

Familial Mediterranean fever

Autoimmunity

Innate immune system

Immunology

Genetics

Medicine

Nature Reviews Rheumatology

Monogenic autoinflammatory diseases are a group of rheumatologic disorders caused by dysregulation in the innate immune system. The molecular mechanisms of these disorders are linked to defects in inflammasome-mediated, NF-κB-mediated or interferon-mediated inflammatory signalling pathways, cytokine receptors, the actin cytoskeleton, proteasome complexes and various enzymes. As with other human disorders, disease-causing variants in a single gene can present with variable expressivity and incomplete penetrance. In some cases, pathogenic variants in the same gene can be inherited either in a recessive or dominant manner and can cause distinct and seemingly unrelated phenotypes, although they have a unifying biochemical mechanism. With an enhanced understanding of protein structure and functionality of protein domains, genotype–phenotype correlations are beginning to be unravelled. Many of the mutated proteins are primarily expressed in haematopoietic cells, and their malfunction leads to systemic inflammation. Disease presentation is also defined by a specific effect of the mutant protein in a particular cell type and, therefore, the resulting phenotype might be more deleterious in one tissue than in another. Many patients present with the expanded immunological disease continuum that includes autoinflammation, immunodeficiency, autoimmunity and atopy, which necessitate genetic testing. Monogenic autoinflammatory diseases are linked to various germline and somatic pathogenic variants but numerous factors must be considered to explain their large phenotypic variability. This Review discusses genotype–phenotype relationships and the potential molecular mechanisms that might explain this variability.

Molecular mechanisms of phenotypic variability in monogenic autoinflammatory diseases