Reclassification of an FBN1 variant emphasizes the importance of segregation analysis, information sharing, and multidisciplinary teamwork in understanding genetic variants in health and disease

Marfan syndrome (MFS) is a complex connective tissue disorder characterized by considerable clinical variability. The diagnosis of MFS is based on the Ghent criteria, which require the presence of both clinical and genetic features. MFS is primarily caused by pathogenic alterations in FBN1, which encodes the fibrillin-1 protein. Fibrillin-1 comprises multiple domains rich in cysteine residues, with disulfide bonds formed between these residues. It has long been recognized that variants that alter or introduce cysteine residues damage protein function, leading to the development of MFS. In this study, we report a cysteine-introducing variant: FBN1 variant, c.6724C>T (p.[Arg2242Cys]). We have observed this variant in several individuals without MFS, challenging our previous understanding of the underlying mechanism of MFS. This finding emphasizes the importance of revisiting and reevaluating our current knowledge in light of new and unexpected observations. Moreover, our study highlights the significance of incorporating local and national data on allele frequencies, as well as employing multidisciplinary phenotyping approaches, in the classification of genetic variants. By considering a wide range of information, we can enhance the accuracy and reliability of variant classification, ultimately improving the diagnosis and management of individuals with genetic disorders like MFS.