Key result
cDNA sequencing and linkage analysis identified a deep intronic point mutation in intron 56 of the FBN1 gene in a genetically unsolved Marfan syndrome family.
Why the study?
Can cDNA sequencing or whole-genome sequencing identify FBN1 mutations in Marfan syndrome cases that are genetically unsolved by standard genomic testing?
Case Report
Can cDNA sequencing or whole-genome sequencing identify FBN1 mutations in Marfan syndrome cases that are genetically unsolved by standard genomic testing?
Deep intronic mutations in FBN1 can cause Marfan syndrome and may explain genetically unsolved cases, highlighting the need for cDNA or whole-genome sequencing when standard genomic testing is negative.
May warrant cDNA sequencing in unsolved Marfan cases; hypothesis-generating for broader clinical adoption.
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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Gillis et al. (2014) conducted a case report in Marfan syndrome. cDNA sequencing and linkage analysis vs. Standard genomic DNA testing was evaluated on Identification of genetic mutation. cDNA sequencing and linkage analysis identified a deep intronic point mutation in intron 56 of the FBN1 gene in a genetically unsolved Marfan syndrome family.
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