DNA Tests

FBN1 gene and mutations

Genes that encode proteins act as guidelines for their production. The information in the DNA is stored as a code composed of four chemical bases: adenine (A), guanine (G), cytosine (C) and thymine (T). Human DNA contains approximately 3 billion bases. The order (sequence) of these bases determines which amino acids and in which order they form the protein.

The FBN1 gene is one of the largest human genes, containing 237,483 bases. The information for fibrillin formation is determined "only" by about 10,000 bases, but they are distributed in 65 coding regions (exons). Most of the mutations in this gene arise because one base is exchanged for another, less often it happens that one or more bases are lost (deletion) or extra bases are inserted at a certain position (duplication). In this way, the instructions for making a protein will change, just as changing the order of alphabet letters and punctuation marks changes the meaning of words and sentences. A person with MFS has one allele of the gene healthy and the other mutant (heterozygote). Very rarely, he has both alleles mutated (homozygote) and only if they are inherited from parents who both have MFS.

According to pathogenesis, mutations are divided into two groups. About 2/3 of all mutations are those with a dominant-negative effect. This results in abnormal fibrillin which incorrectly interacts with normal fibrillin (which is encoded by the second, healthy allele) to form microfibrils, and abnormal fibrillin has altered amino acids important for the binding of growth factors and other extracellular matrix components. As a result, the structure of the fibers is altered and their interaction with the extracellular matrix components is impaired. About 1/3 of the mutations result in haploinsuficiency. In this case, the mutated allele causes the formation of truncated fragments of fibrillin, or the protein is not formed at all. However, the amount of fibrillin that is encoded by the healthy allele is insufficient, resulting in the formation of weak tissues unable to perform their functions.

DNA tests and Marfan syndrome

The tests should be carried out if indicated by a clinical geneticist. DNA molecules are obtained from the patient’s blood which also contain the FBN1 gene for fibrillin responsible for Marfan syndrome. By means of special methods, mutations are detected in genes.

Problems of DNA tests:

1/ Most FBN1 mutations are unique to an individual or family with Marfan. At the same time, due to the high number of unique mutations and the wide variety of clinical features for the same mutation, knowledge of the particular type and position of the mutation in the gene can only predict very little the development and severity of the disease.

2/ Tests used so far have not found a mutation in the FBN1 gene in 100% of patients with a clear manifestation of Marfan syndrome.

3/ Mutations in the FBN1 gene cause not only Marfan but also other diseases (eg Shprintzen-Goldberg syndrome, MASS syndrome, familial ectopia lentis, autosomal dominant Weill-Marchesani syndrome).

More than 1800 FBN1 mutations are currently identified. These can occur at virtually any point in the gene. Given the size of the gene and the breakdown of the coding DNA into 65 exons, the methods of analysis are costly and time consuming. Therefore, DNA tests for Marfan syndrome are used in certain cases where the patient does not show standard phenotypic features or for screening family members. Mutation identification in a person with MFS is required for prenatal diagnosis or preimplantation genetic diagnosis (PGD).