title: An FBN1 deep intronic mutation in a familial case of Marfan syndrome: an explanation for genetically unsolved cases?
abstract: Marfan syndrome (MFS) is caused by mutations in the FBN1 (fibrillin-1) gene, but approximately 10% of MFS cases remain genetically unsolved. Here, we report a new FBN1 mutation in an MFS family that had remained negative after extensive molecular genomic DNA FBN1 testing, including denaturing high-performance liquid chromatography, Sanger sequencing, and multiplex ligation-dependent probe amplification. Linkage analysis in the family and cDNA sequencing of the proband revealed a deep intronic point mutation in intron 56 generating a new splice donor site. This mutation results in the integration of a 90-bp pseudo-exon between exons 56 and 57 containing a stop codon, causing nonsense-mediated mRNA decay. Although more than 90% of FBN1 mutations can be identified with regular molecular testing at the genomic level, deep intronic mutations will be missed and require cDNA sequencing or whole-genome sequencing.
authors.affiliation: Center for Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Gillis
authors.forename: Marlies
authors.initials: M
authors.lastname: Kempers
authors.forename: Simone
authors.initials: S
authors.lastname: Salemink
authors.forename: Janneke
authors.initials: J
authors.lastname: Timmermans
authors.forename: Emile C
authors.initials: EC
authors.lastname: Cheriex
authors.forename: Sebastiaan C A M
authors.initials: SC
authors.lastname: Bekkers
authors.forename: Erik
authors.initials: E
authors.lastname: Fransen
authors.forename: Christine E M
authors.initials: CE
authors.lastname: De Die-Smulders
authors.forename: Bart L
authors.initials: BL
authors.lastname: Loeys
authors.forename: Lut
authors.initials: L
authors.lastname: Van Laer
mesh_terms: D000328:Adult; D000368:Aged; D002675:Child, Preschool; D005091:Exons; D000071838:Fibrillin-1; D000071837:Fibrillins; D006801:Humans; D007438:Introns; D008297:Male; D008382:Marfan Syndrome / Q000235:genetics* / Q000473:pathology; D008840:Microfilament Proteins / Q000235:genetics*; D008875:Middle Aged; D010375:Pedigree; D017354:Point Mutation; D054392:Adipokines
chemical_list: D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; C000605722:FBN1 protein, human; D054392:Adipokines
keywords: FBN1; Marfan syndrome; deep intronic mutation; pseudo-exon