Characterization of Two Novel Intronic Variants Affecting Splicing in FBN1-Related Disorders

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.