Abstract
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.
Key points
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Mendelian-inherited pathogenic variants in a given gene can have different inheritance patterns and can cause distinct and sometimes opposing clinical phenotypes.
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Pathogenic variants in the same gene can have variable disease expressivity depending on their effect on protein function.
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Pathogenic variants in different genes can result in a similar phenotype by virtue of converging on the same signalling pathway (as exemplified by the spectrum of phenotypes denoted as familial cold autoinflammatory syndromes (FCAS).
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A growing number of autoinflammatory diseases can be explained by non-Mendelian inheritance of somatic variants.
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Although systemic inflammation and fevers are common features of autoinflammatory diseases, specific organ manifestations are determined by the tissue expression of mutated proteins.
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Other genetic alleles and risk factors, such as infections and stress, also contribute to the phenotypic variability of autoinflammatory diseases.
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Glossary
- Monogenic
-
A phenotype or disease that is caused by variation in a single gene and has well-defined inheritance pattern.
- Phenotype
-
An organism’s observable traits such as height, hair colour or blood type.
- Null alleles
-
Genetic changes that cause a complete lack of protein expression or can notably alter protein function.
- Somatic variants
-
Genetic alterations that occur post-zygotic in somatic cells (for example, leukocytes and keratinocytes) and are not passed on to children.
- Genotype
-
An organism’s complete set of genetic material; this term can be used to refer to the variants of a single gene or a set of variants in multiple genes.
- Mendelian
-
The manner by which genes and traits are passed from parents to their offspring, described by Gregor Mendel.
- Oligogenic
-
A phenotype or disease that is dependent on a few genes and is an intermediate between monogenic and polygenic inheritance.
- Dominant
-
The type of inheritance pattern referring to when a single copy of the altered gene is sufficient to cause disease or express the trait.
- Recessive
-
A type of inheritance pattern referring to when both copies of a gene are required for the phenotype or disease expressivity.
- Biallellic
-
A term used to refer to both alleles of a single gene or gene locus (both paternal and maternal).
- Missense variants
-
Genetic changes in a single nucleotide that might or might not result in the substitution of one amino acid for another in the protein.
- Hypermorphic variants
-
A type of genetic change (also known as a gain-of-function mutation) where the altered gene product has an increased level of activity or is expressed at higher levels. These mutations are typically dominantly inherited.
- Monoallelic
-
A term used to refer to when only one of the two copies of a particular gene (alleles) is actively expressed and the other allele is silent.
- Heterozygous
-
An individual who has two different alleles of a particular gene.
- Polygenic
-
A phenotype or disease that is influenced by several genes and often by environmental factors.
- Prenylation
-
A post-translational modification that involves covalent attachment of a lipid consisting of either three (farnesyl) or four (geranylgeranyl) isoprene units to a cysteine residue at or near the C terminus of a protein.
- Hypomorphic variants
-
A type of genetic change (also known as loss-of-function mutation) where the altered gene product has decreased activity or expression. These mutations are typically recessively inherited.
- Nonsense mutation
-
A genetic change that causes the translation of a protein to terminate earlier than would occur with the wild-type gene.
- Homozygous
-
An individual who has inherited the identical alleles of a particular gene from both parents.
- De novo
-
A genetic change that arises in a germ cell or fertilized egg and is not inherited from the parents.
- Disease expressivity
-
The extent to which a genotype shows its phenotypic expression in different people with the same genetic disease.
- Digenic
-
A phenotype or disorder that is expressed only when two non-allelic controlling genes interact.
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Aksentijevich, I., Schnappauf, O. Molecular mechanisms of phenotypic variability in monogenic autoinflammatory diseases. Nat Rev Rheumatol 17, 405–425 (2021). https://doi.org/10.1038/s41584-021-00614-1
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DOI: https://doi.org/10.1038/s41584-021-00614-1
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