Multi-exon out of frame deletion of the FBN1 gene leading to a severe juvenile onset cardiovascular phenotype in Marfan syndrome

Marfan syndrome is caused by mutations in fibrillin-1, a large gene spanning ∼ 200 kb of genomic DNA on chromosome 15q21. So far, more than 600 different mutations have been identified, accounting for 60–90% of all Marfan syndrome cases, the vast majority being single nucleotide exchanges as well as small deletions and insertions. Only four major rearrangements have been described in the literature so far. We have screened 11 individuals fulfilling the diagnostic criteria of Marfan syndrome but negative for point mutations in the fibrillin-1 gene by SSCP and/or direct sequencing, for large rearrangements. We report here the largest known de novo and out of frame deletion in the fibrillin-1 gene in a patient fulfilling the diagnostic criteria of Marfan syndrome. We identified the deletion breakpoints at the genomic and transcript levels and studied the expression of the mutated allele at the transcript and protein level. We conclude that large rearrangements may account for a non-negligible proportion of all Marfan cases.