Abstract
BackgroundMarfan syndrome (MFS) is an autosomal dominant connective tissue disorder caused by mutations in the FBN1 gene. Approximately 90% of classic MFS patients have a FBN1 mutation that can be identified by single-gene sequencing or gene-panel sequencing targeting FBN1. However, a small proportion of MFS patients carry a large genomic deletion in FBN1, which cannot be detected by routine sequencing. Here, we performed an MLPA (multiplex ligation-dependent probe amplification) test to detect large deletions and/or duplications in FBN1 and TGFBR2 in 115 unrelated Chinese patients with suspected MFS or early-onset aneurysm/dissection.ResultsFive novel large deletions encompassing a single exon or multiple exons in the FBN1 gene were characterized in five unrelated patients, of which four were proven by Sanger sequencing, and the breakpoints were identified. Three of them met the revised Ghent criteria when genetic results were not available, and the other two patients were highly suspected and diagnosed with MFS until the FBN1 deletions were identified.ConclusionsOur finding expands the mutation spectrum of large FBN1 deletions and emphasizes the importance of screening for large FBN1 deletions in clinical genetic testing, especially for those with classic Marfan phenotype.
Highlights
Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder caused by mutations in the FBN1 gene
MFS is caused by mutations in the FBN1 gene, which is located on chromosome 15q21.1 and encodes a 320-kDa extracellular matrix glycoprotein fibrillin-1 [2, 3], a major component of microfibrils
Sanger sequencing of FBN1 and panel sequencing including FBN1 as well as a number of other genes associated with inherited aortopathies are commonly used to identify mutations [6]; both of these methods have a limitation for detecting FBN1 large deletions or duplications, which have been reported in up to 7% of MFS patients [7]
Summary
Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder caused by mutations in the FBN1 gene. 90% of classic MFS patients have a FBN1 mutation that can be identified by singlegene sequencing or gene-panel sequencing targeting FBN1. A small proportion of MFS patients carry a large genomic deletion in FBN1, which cannot be detected by routine sequencing. Sanger sequencing of FBN1 and panel sequencing including FBN1 as well as a number of other genes associated with inherited aortopathies are commonly used to identify mutations [6]; both of these methods have a limitation for detecting FBN1 large deletions (del) or duplications (dup), which have been reported in up to 7% of MFS patients [7]
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