John Rosendahl Østergaard

Difficulties in diagnosing Marfan syndrome using current FBN1 databases

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PURPOSE: The diagnostic criteria of Marfan syndrome (MFS) highlight the importance of a FBN1 mutation test in diagnosing MFS. As genetic sequencing becomes better, cheaper, and more accessible, the expected increase in the number of genetic tests will become evident, resulting in numerous genetic variants that need to be evaluated for disease-causing effects based on database information. The aim of this study was to evaluate genetic variants in four databases and review the relevant literature.

METHODS: We assessed background data on 23 common variants registered in ESP6500 and classified as causing MFS in the Human Gene Mutation Database (HGMD). We evaluated data in four variant databases (HGMD, UMD-FBN1, ClinVar, and UniProt) according to the diagnostic criteria for MFS and compared the results with the classification of each variant in the four databases.

RESULTS: None of the 23 variants was clearly associated with MFS, even though all classifications in the databases stated otherwise.

CONCLUSION: A genetic diagnosis of MFS cannot reliably be based on current variant databases because they contain incorrectly interpreted conclusions on variants. Variants must be evaluated by time-consuming review of the background material in the databases and by combining these data with expert knowledge on MFS. This is a major problem because we expect even more genetic test results in the near future as a result of the reduced cost and process time for next-generation sequencing.Genet Med advance online publication 26 March 2015Genetics in Medicine (2015); doi:10.1038/gim.2015.32.

Original languageEnglish
JournalGenetics in Medicine
Publication statusPublished - 26 Mar 2015

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