Author(s):
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Gillis, E.; Kempers, M.; Salemink, S.;
Timmermans, J.
; Cheriex, E.C.; Bekkers, S.C.; Fransen, E.; Die-Smulders, C.E.M. de;
Loeys, B.L.
; Laer, L. van
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Subject:
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Radboudumc 0: Other Research RIHS: Radboud Institute for Health Sciences Radboudumc 0: Other Research RIMLS: Radboud Institute for Molecular Life Sciences |
Abstract:
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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.
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