Abstract
FBN1 encodes fibrillin 1, a key structural component of the extracellular matrix, and its variants are associated with a wide range of hereditary connective tissues disorders, such as Marfan syndrome (MFS) and mitral valve–aorta–skeleton–skin (MASS) syndrome. Interpretations of the genomic data and possible genotype–phenotype correlations in FBN1 are complicated by the high rate of intronic variants of unknown significance. Here, we report two unrelated individuals with the FBN1 deep intronic variants c.6872-24T>A and c.7571-12T>A, clinically associated with MFS and MASS syndrome, respectively. The individual carrying the c.6872-24T>A variant is positive for aortic disease. Both individuals lacked ectopia lentis. In silico analysis and subsequent mRNA study by RT-PCR demonstrated the effect of the identified variant on the splicing process in both cases. The c.6872-24T>A and c.7571-12T>A variants generate the retention of intronic nucleotides and lead to the introduction of a premature stop codon. This study enlarges the mutation spectrum of FBN1 and points out the importance of intronic sequence analysis and the need for integrative functional studies in FBN1 diagnostics.
Highlights
The FBN1 gene is located in 15q21.1 and includes 65 exons which encode for fibrillin 1, a large glycoprotein constituted by 47 cysteine-rich epidermal growth factor (EGF)-like domains and seven motifs homologous to the binding protein for transforming growth factor beta (TGFβ) [1,2]
Molecular testing was carried out on the Individual 1 DNA by Sanger sequencing of the FBN1 gene, and this gave normal results
Molecular studies revealed that the novel c.6872-24T>A and c.7571-12T>A FBN1 variants induce aberrant pre-mRNA splicing by the generation of a new cryptic acceptor site that outcompetes the canonical splice site and generate exonization of intronic sequences
Summary
The FBN1 gene is located in 15q21.1 and includes 65 exons which encode for fibrillin 1, a large glycoprotein constituted by 47 cysteine-rich epidermal growth factor (EGF)-like domains and seven motifs homologous to the binding protein for transforming growth factor beta (TGFβ) [1,2].Fibrillin 1 is a major structural component of the extracellular matrix microfibrils and gives stability and elasticity to many tissues [2]. The FBN1 gene is located in 15q21.1 and includes 65 exons which encode for fibrillin 1, a large glycoprotein constituted by 47 cysteine-rich epidermal growth factor (EGF)-like domains and seven motifs homologous to the binding protein for transforming growth factor beta (TGFβ) [1,2]. Variants in FBN1 cause a wide range of autosomal dominant heritable connective tissue disorders, including Marfan syndrome Over 1800 different FBN1 germline variants have been identified so far (UMD-FBN1, http://www.umd.be/FBN1/) [4,5] and only a few genotype–phenotype correlations are available [6,7]. Nonsense, frameshift, and some splicing variants appear correlated with a more severe skin and skeletal phenotype, as compared to in-frame variants [8].
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