Abstract
BackgroundConnective tissue diseases characterized by aortic aneurysm, such as Marfan syndrome, Loeys-Dietz syndrome and Ehlers Danlos syndrome type IV are heterogeneous and despite overlapping phenotypes, the natural history, clinical manifestations and interventional course for each diagnosis can be quite unique. The majority of mutations involved in the etiology of these disorders are missense and nonsense mutations. However, large deletions and duplications undetected by sequencing may be implicated in their pathogenesis, and may explain the apparent lack of genotype-phenotype correlation in a subset of patients. The objective of this study was to search for large pathogenic deletions and/or duplications in the FBN1, TGFβR1, and TGFβR2 genes using multiplex-ligation dependent probe amplification (MLPA) in patients with aortopathy, in whom no mutations in the FBN1, TGFβR1, and TGFβR2 genes were identified by sequencing.MethodsThe study included 14 patients from 11 unrelated families with aortic aneurysm. Of those, six patients (including 3 first-degree relatives), fulfilled the revised Ghent criteria for Marfan syndrome, and eight had predominantly aortic aneurysm/dilatation with variable skeletal and craniofacial involvement. MLPA for FBN1, TGFβR1, and TGFβR2 was carried out in all patients. A 385 K chromosome 15 specific array was used in two patients with a deletion of the entire FBN1 in order to define its size and boundaries.ResultsWe identified two novel large deletions in the FBN1 gene in four patients of two unrelated families who met clinical diagnostic criteria for Marfan syndrome. One patient was found to have a FBN1 deletion encompassing exons 1-5. The other three patients had a 542 Kb deletion spanning the whole FBN1 gene and five additional genes (SLC24A5, MYEF2, CTXN2, SLC12A1, DUT) in the chromosome 15.ConclusionsOur findings expand the number of large FBN1 deletions, and emphasize the importance of screening for large genomic deletions in connective tissue disorders featuring aortopathies, especially for those with classic Marfan phenotype.
Highlights
Connective tissue diseases characterized by aortic aneurysm, such as Marfan syndrome, Loeys-Dietz syndrome and Ehlers Danlos syndrome type IV are heterogeneous and despite overlapping phenotypes, the natural history, clinical manifestations and interventional course for each diagnosis can be quite unique
In our study, we identified two novel large deletions in the FBN1 gene in four patients of two unrelated families who met clinical diagnostic criteria for Marfan syndrome
History was remarkable for a diagnosis of Marfan syndrome in the mother, who died secondary to complications from surgery for aortic root dissection years prior, and one 30-year-old affected brother, who was unavailable for molecular testing
Summary
Connective tissue diseases characterized by aortic aneurysm, such as Marfan syndrome, Loeys-Dietz syndrome and Ehlers Danlos syndrome type IV are heterogeneous and despite overlapping phenotypes, the natural history, clinical manifestations and interventional course for each diagnosis can be quite unique. Mutations in genes related to the structure and function of the aortic wall, such as MYH11 on chromosome 16p12.2-13.3 [2,3], ACTA2 on chromosome 10q23-24 [4], SLC2A10 on Recently, a new syndrome presenting with aneurysms, dissections and tortuosity throughout the arterial tree and mild craniofacial features, early-onset osteoarthritis and skeletal and cutaneous anomalies was described to be associated with mutations in the SMAD3 [10] These conditions have broad spectrum of phenotypic expression and overlapping phenotype, their natural history and interventional course can be quite unique. Sequencing does not detect large exonic deletions or duplications unless quantitative methods are applied, which allegedly could explain the lack of genotype-phenotype correlation in some patients
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