Difficulties in diagnosing Marfan syndrome using current FBN1 databases

Abstract

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 timeconsuming 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.

A novel molecular diagnostics platform for somatic and germline precision oncology

“…We also detected several variants listed at the moment of clinical interpretation of results by HGMD as pathogenic (disease causing mutation or DM) but, in our view, with controversial or insufficient support in 41.67% of the cases (15/36; based on Tier-1 genes only), which is in agreement with previous observations (Olfson et al 2015;Groth et al 2016). We classified these variants as "DM-Controversial" and reported them under the "uncertain clinical significance variants" category, separated from the robust pathogenic variants.…”

“…In our series of 36 cases analyzed by our germline subpanel and considering only genes in Tier-1, 15 cases (41.67%) had variants that were classified as disease causing mutations by HGMD but were degraded to DM-Controversial after expert review. This is in agreement with previous reports (Olfson et al 2015;Groth et al 2016). We recommend performing clinical interpretation by carefully reviewing those publications supporting the HGMD and/or ClinVar classifications.…”

“…; Groth et al. ). We classified these variants as “DM‐Controversial” and reported them under the “uncertain clinical significance variants” category, separated from the robust pathogenic variants.…”

“…; Groth et al. ). We recommend performing clinical interpretation by carefully reviewing those publications supporting the HGMD and/or ClinVar classifications.…”

Marfan syndrome database information unreliable for diagnoses

“…MFS is an autosomal dominant disorder caused by variants in FBN1, which expresses a protein important to connective tissue. An analysis by researchers from Aarhus University Hospital in Denmark found that none of the 23 variants listed as causing MFS in four commonly used genetic databases were clearly associated with the disease, according to a recent paper in Genetics in Medicine (Groth et al, ).…”