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Identification of gross deletions in FBN1 gene by MLPA.

ABSTRACT: BACKGROUND:Marfan 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. RESULTS:Five 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. CONCLUSIONS:Our 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.

SUBMITTER: Yang H

PROVIDER: S-EPMC6172713 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Identification of gross deletions in FBN1 gene by MLPA.

Yang Hang H Ma Yanyun Y Luo Mingyao M Zhao Kun K Zhang Yinhui Y Zhu Guoyan G Sun Xiaogang X Luo Fanyan F Wang Lin L Shu Chang C Zhou Zhou Z

Human genomics 20181004 1

<h4>Background</h4>Marfan 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 t ...[more]

PMID: 30286810

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Project description: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. 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, TGF?R1, and TGF?R2 genes using multiplex-ligation dependent probe amplification (MLPA) in patients with aortopathy, in whom no mutations in the FBN1, TGF?R1, and TGF?R2 genes were identified by sequencing.The 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, TGF?R1, and TGF?R2 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.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. 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.Our 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.

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Identification of gross deletions in FBN1 gene by MLPA.

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Identification of gross deletions in FBN1 gene by MLPA.

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