Gross deletions in FBN1 results in variable phenotypes of Marfan syndrome

A mutation in FBN1 is primarily attributed to Marfan syndrome (MFS). So far, >1800 unique FBN1 mutations have been identified, with the vast majority being single-nucleotide substitutions, small deletions, and insertions. The rearrangement of large fragments of FBN1 accounts for only 1.7% of all variants. The aim of this study was to investigate the characteristics of large genomic rearrangements in FBN1 among MFS patients and to evaluate the correlations between genotype and phenotype.

Systematic sequencing of the disease-related genes FBN1, TGFBR1, and TGFBR2, was carried out previously for 26 unrelated patients with MFS. No small mutations were found. Subsequently, multiplex ligation-dependent probe amplification was performed for the detection of copy number variations in these patients. The breakpoints were determined by gap PCR and sequencing. Transcription level analysis was conducted in patients whose RNA sample was available.

Four gross deletions were identified in FBN1. Three deletions (exons 6, 48-53, and 49-50) were predicted to be in-frame deletions; the remaining deletion (exons 1-36) was expected to induce the loss of one copy of the FBN1 gene. The breakpoints of these four deletions were cloned, and revealed deletion sizes of 16,551, 10,346, 4563, and 187,047bp, respectively. Patients with in-frame deletions of exons 48-53 and 49-50 showed severe clinical phenotypes; Patient with an exon 6 deletion showed mild potential MFS phenotypes. And the patient had classic MFS with a deletion of exons 1-36.

We characterized four large genomic rearrangements in FBN1. FBN1 haploinsufficiency correlated with a classic MFS phenotype, while in-frame deletions between exons 24-53 of FBN1 tended to cause severe clinical phenotypes.