Correlation between large FBN1 deletions and severe cardiovascular phenotype in Marfan syndrome: Analysis of two novel cases and analytical review of the literature

Marfan syndrome (MFS) is a clinically heterogeneous hereditary connective tissue disorder. Severe cardiovascular manifestations (i.e., aortic aneurysm and dissection) are the most life-threatening complications. Most of the cases are caused by mutations, a minor group of which are copy number variations (CNV), in the FBN1 gene.Multiplex ligation-dependent probe amplification test was performed to detect CNVs in 41 MFS patients not carrying disease-causing mutations in FBN1 gene. Moreover, the association was analyzed between the localization of CNVs, the affected regulatory elements and the cardiovascular phenotypes among all cases known from the literature.A large two-exon deletion (exon 46 and 47) was identified in two related patients, which was associated with a mild form of cardiovascular phenotype. Severe cardiovascular symptoms were found significantly more frequent in patients with FBN1 large deletion compared to our patients with intragenic small scale FBN1 mutation. Bioinformatic data analyses of regulatory elements located within the FBN1 gene revealed an association between the deletion of STAT3 transcription factor-binding site and cardiovascular symptoms in five out of 25 patients.Our study demonstrated that large CNVs are often associated with severe cardiovascular manifestations in MFS and the localization of these CNVs affect the phenotype severity.