An FBN1 deep intronic mutation in a familial case of Marfan syndrome: an explanation for genetically unsolved cases?

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Title:	An FBN1 deep intronic mutation in a familial case of Marfan syndrome: an explanation for genetically unsolved cases?
Author(s):	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
Publication year:	2014
Source:	Human Mutation, vol. 35, iss. 5, (2014), pp. 571-574
ISSN:	1059-7794
DOI:	https://doi.org/10.1002/humu.22540
Publication type:	Article / Letter to editor
Please use this identifier to cite or link to this item : http://hdl.handle.net/2066/134037
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Subject:	Radboudumc 0: Other Research RIHS: Radboud Institute for Health Sciences Radboudumc 0: Other Research RIMLS: Radboud Institute for Molecular Life Sciences
Organization:	Cardiology Human Genetics
Journal title:	Human Mutation
Volume:	vol. 35
Issue:	iss. 5
Page start:	p. 571
Page end:	p. 574
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.