Detection of large genomic deletions of FBN1 and confirmation of breakpoints in Marfan syndrome patients with negative results in next-generation sequencing

Marfan syndrome (MFS) is an autosomal dominant genetic disorder caused by mutations in the FBN1 gene. Although point mutations in the FBN1 gene are the main pathogenic mutation types for MFS, large genomic deletions and duplications still play a very important role in MFS. Especially for typical MFS patients with negative results in next-generation sequencing, this study aims to study the breakpoints of large genomic structural variations of the FBN1 gene in this type of patients. Systematic sequencing of FBN1 gene using multiplex ligation dependent probe amplification was performed for 17 unrelated patients with confirmed and/or suspected MFS in China. Sanger sequencing was carried out to confirm the breakpoints. Two novel large deletions encompassing a single exon or multiple exons in the FBN1 gene were characterized in two unrelated patients among the 17 MFS cases. The two deletions (exons 37–38, and 49) exist in the frame of FBN1 gene. The patients with the in-frame deletions of the exons 37–38 and 49 exhibited the typical MFS phenotype. Of which two deletions were proven by Sanger sequencing, and the breakpoints were identified. We characterized two large genomic mutations in FBN1 among MFS patients. The in-frame deletions between exons 37–38 and 49 of FBN1 tended to cause severe MFS clinical phenotypes. Our finding also expands the mutation spectrum of FBN1 large deletions and duplications to highlight the importance of FBN1 screening among the patients with classic Marfan phenotype. At the same time, our detection also highlights the importance of Sanger sequencing validation, which remains the gold standard for sequencing technologies.