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Genetic Testing for FBN1 Gene Mutations

written by: Superbwriter•edited by: lrohner•updated: 12/27/2010

The various types of genetic testing for FBN1 gene mutations are presented in this article together with the limitations and usefulness of each procedure.

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    Why Is Genetic Testing For FBN1 Gene Mutations Necessary?

    The FBN1 gene, also known as “fibrillin 1,” is located on the long (q) arm of chromosome 15 at position 21.1. This gene codes for the production of the protein bilbrillin-1 that forms the main constituent of connective tissues everywhere in the body. Mutations in the FBN1 gene either decrease the quantity of fibrillin-1 produced or cause alterations in the structure of fibrillin-1 which is available in the body for the purposes of microfibril formation.

    Researchers have detected over 500 FBN1 mutations that are related to MFS and other FBN1-associated connective tissue disorders. The severity of the symptoms in most of these genetic disorders makes the management very difficult and the prognosis quite poor.

    The most prevalent of the disorders caused by mutations of FBN1 is MFS. MFS is an inherited autosomal dominant disorder and the risk for pregnant mothers transmitting the disease to off-springs is high. As a result, genetic testing for FBN1 gene mutations related disorders is quite important after a clinical diagnosis.Genetic testing for FBN1 gene mutations is done when the primary clinical diagnosis for any patient indicates the incidence of type 1 fibrillinopathies like the Marfan syndrome (MFS), isolated ectopia lentis, Shprintzen-Goldberg craniosynostosis syndrome or MASS syndrome, all of which are genetic disorders caused by mutations in the FBN1 gene.

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    Types of Genetic Testing for FBN1 Gene Mutations

    Direct genetic testing for FBN1 gene mutations is a very complicated and unreliable process for a number of reasons. These include the huge size of the gene, its division into 65 separate exons or coding sections, the vast distribution of mutations alongside the entire length of the gene and the unique diversity in the kinds of mutations which have been known to occur. When a family needs genetic testing for FBN1 gene mutations and counselling, this complex process has to be undertaken.

    Sequence analysis, or mutation scanning, performs scanning of all 65 FNB1 exons conducted using a variety of techniques. The mutation detection rates vary from 70% to 93%. Sequence analysis of cDNA instead of genomic DNA provides time-efficient screening of the full FBN1 coding region. It also allows detection of some splice mutations which can’t be detected by sequence analysis of gDNA. At present, sequence analysis and mutation scanning are the most widely used methods for genetic testing for FBN1 gene mutations. The mutation detection rate of FBN1 mutation scanning and cDNA sequence analysis are only 70% to 93% accurate. This accuracy is also dependent on the accuracy of the clinical diagnosis and the type of mutation as some genetic alterations are not detected by these testing techniques.

    Deletion analysis is another method used to carry out genetic testing for FBN1 gene mutations. Clinical laboratories carry out additional assays with the aim of detecting big deletions if sequence analysis or mutation scanning results turn out to be negative. The yield in persons with Marfan syndrome without a defined coding sequence or splice site mutation remains to be elucidated. Last but not the least, linkage analysis can be utilized to check if a person has inherited an FBN1 allele which is related to the incidence of any FBN1 genetic disorder in family members. The costs incurred in the genotyping of several family members and the much higher efficiency of gDNA sequencing had made the current use of linkage analysis very limited. Also, linkage testing is not available to families that have just one diagnosed member is affected. Also, the use of linkage analysis needs to be exercised with great caution, especially if there is exhibition of atypical phenotypes as this suggests a clinical overlap with genetic disorders not associated with mutations in the FBN1 gene.

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    Limitations In the Use of Genetic Testing For FBN1 Gene Mutations

    Although several methods are available for genetic testing for FBN1 gene mutations, none of the current methods used clinically is able to identify all mutations types. Also since mutations of the fibrillin-1 gene can cause several genetic disorders, it is always difficult to predict accurately what condition to expect when a certain mutation is detected. Also, family members who have the same mutation sometimes exhibit variations in the expression of the gene and show different timings of onset of disorders as well as the severity of the disease. Thus, the use of genetic testing for FBN1 gene mutations is still not the primary way of screening for genetic disorders.

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    References:

    1) Lapini, Attanasio M., et al. (2008). “FBN1 mutation screening of patients with Marfan syndrome and related disorders: detection of 46 novel FBN1 mutations.” Clinical Genetics, Vo. 74, 2008, pp.39-46.

    2) Howarth, Rachel, et al. (2007). “Application of dHPLC for Mutation Detection of the Fibrillin-1 Gene for the Diagnosis of Marfan Syndrome in a National Health Service Laboratory.” Genetic Testing, Vol. 11, No. 2, 2007, pp. 146-152.

    3) U.S. Department of Health & Human Services, National Institutes of Health, National Heart Lung and Blood Institute. Retrieved on December 21st, 2010 from: http://www.nhlbi.nih.gov/health/dci/Diseases/mar