What is genetics?

Genetics is the science of genes. Genes are important because they contain all the information the body needs to work properly. Genes are made up of building blocks called nucleotides. Each nucleotide is characterized by one of four organic bases: adenine (A), guanine (G), cytosine (C) and thymine (T). All nucleotides together form the DNA, that is divided into chromosomes. The DNA of each individual is unique; the result of the combination of the DNA of one’s parents. The only exception to this rule are identical twins: their DNA is exactly the same.

DNA differs from person to person: this phenomenon is called genetic variation and is completely normal. When there is a change in the sequence of the building blocks of a gene, we call this a mutation. Mutations can be either disease-causing or non-disease-causing. In the first case, mutations lead to a disease, in the second case the carrier in question is not affected by it. While we do know how a mutation occurs, we don’t always know why it happens. Often it is just by chance. However, a new mutation can be passed down from parent to child.

Not all diseases are inherited in the same way. Within the monogenic diseases (disorders caused by mutations in a single gene) we can make a distinction between so-called dominant, recessive and X-linked inheritance. Monogenic autoinflammatory disorders usually involve autosomal dominant and autosomal recessive inheritance. To understand what exactly these terms mean, it is important to know how genetic information is transmitted. We all have two copies of a gene, one coming from our mother and the other from our father. In the case of dominant inheritance, a mutation only needs to be present on one of the two gene copies to lead to the disease. This means that if one of the parents has the disease, each child has a 50% chance of inheriting the disease.

In contrast, two mutated gene-copies are needed for the manifestation of a recessive disorder. A person who has the mutation on only one of the two gene copies is called a healthy carrier. If two healthy carriers have a child together, there is a 50% chance that the child will also be a healthy carrier, a 25% chance that the mutation will not be present at all and a 25% chance of disease.

Having a mutation does not always mean that a person will also become ill. The probability that a particular mutation will be expressed is referred to in genetics as penetrance. If the penetrance is 100%, all persons with the mutation will develop the disease. If the penetrance is incomplete, only a proportion of the people with the mutation will get the disease. In the group of autoinflammatory disorders, there is a lot of variation when it comes to penetrance. TRAPS is a good example of this. Some of these mutations have a high penetrance, while others have a very low penetrance. It is important to realize that in the case of low penetrance, people within one family with the same mutation may or may not have symptoms of the disease.

When it comes to the genetics of autoinflammatory disorders, there are two main groups: the monogenic disorders and the diseases caused by mutations in multiple genes or of which the origin is not yet known. The following disorders are the result of mutation(s) in a single gene: FMF, TRAPS, HIDS, CAPS, DIRA, Blau syndrome, PAPA, Majeed syndrome and NLRP12 syndrome. Of these, TRAPS, CAPS, Blau syndrome, PAPA and NLRP12 syndrome are inherited in an autosomal dominant manner. FMF, HIDS, DIRA and Majeed syndrome are examples of disorders with an autosomal recessive inheritance pattern.

The second group of disorders includes sJIA, juvenile spondyloarthropathies, CRMO, and Schnitzler’s syndrome. The cause of sJIA, juvenile spondyloarthropathies is much more complex than that of the monogenic disorders. Little is still known about the cause of CRMO, juvenile spondyloarthropathies and Schnitzler syndrome. It is important to note that in addition to genetic factors, environmental factors also play a significant role in the development of autoinflammatory diseases.