Identification of gross deletions in FBN1 gene by MLPA

Yang, Hang; Ma, Yanyun; Luo, Mingyao; Zhao, Kun; Zhang, Yinhui; Zhu, Guofu; Sun, Xiaogang; Luo, Fanyan; Wang, Lin; Shu, Chang; Zhou, Zhou

doi:10.1186/s40246-018-0178-y

Cited by 16 publications

(18 citation statements)

References 16 publications

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“…Yang and his colleagues applied MLPA for 115 samples that came back negative after a 15-gene panel. As a result, they found 5 large deletions in the FBN1 gene (4.3%) [ 45 ]. Consistently with our previous study, these findings highlight the importance of CNV screening in point-mutation negative cases, to increase the detection rate of disease-causing genetic variants [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

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Optimising the mutation screening strategy in Marfan syndrome and identifying genotypes with more severe aortic involvement

Stengl

Bors

Ágg

et al. 2020

Orphanet J Rare Dis

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Background Marfan syndrome (MFS) is a systemic connective tissue disorder with life-threatening manifestations affecting the ascending aorta. MFS is caused by dominant negative (DN) and haploinsufficient (HI) mutations of the FBN1 gene. Our aim was to identify mutations of MFS patients with high detection rate and to investigate the use of a gene panel for patients with Marfanoid habitus. We also aimed to examine correlations between genotype and cardiovascular manifestations to predict “malignant” mutations. Methods 136 individuals were enrolled. In the first phase, next-generation sequencing (NGS) and Sanger sequencing were performed for 57 patients to screen the FBN1 gene, followed by multiplex ligation-dependent probe amplification (MLPA) in negative cases. For repeated negative results, NGS gene panel involving 9 genes was used. In the second phase, 79 patients were tested primarily with the same gene panel, negative samples were tested by MLPA. Results 84 pathogenic mutations were detected, out of which 78 affected FBN1, 6 non-FBN1 mutations (2 TGFB2, 1 TGFBR2, 2 TGFBR1, 1 SMAD3) are associated with Loeys-Dietz syndrome (LDS). LDS patients had lower systemic score and they were younger, but their aortic involvement did not differ. MLPA detected 4 multi-exon deletions of FBN1 gene, which could not be identified by our first-step screening method. Aortic involvement (aortic dissection and/or dilation) did not differ significantly among HI and DN mutations (p = 0.061). Combined group of HI and DN mutations eliminating a disulphide-bonding cysteine (DN Cys) had significantly higher aortic involvement rate than DN mutations not eliminating a disulphide-bonding cysteine (DN non-Cys) (p < 0.001). Patients with DN Cys required significantly more aortic surgeries than HI and DN non-Cys mutations (p = 0.042 and p = 0.015, respectively). Conclusions Due to the relevant number of mutations affecting genes other than FBN1, preferred approach for testing individuals with Marfanoid habitus is using a gene panel rather than single-gene analysis, followed by MLPA for negative samples. DN Cys and HI mutations should be considered as risk factors for aortic involvement. Genetic testing for patients with Marfanoid features and a systemic score under 7 is recommended, as LDS patients may have lower scores, but they may have severe cardiovascular manifestations.

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Section: Discussionmentioning

confidence: 99%

“…It was 43(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51) years in the DN Cys-, 34(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40) years in the DN non-Cys-and 38(34)(35)(36)(37)(38)(39)(40)(41) years in the HI group (DN Cys vs DN non-Cys p = 0.074; DN Cys vs HI p = 0.151; DN non-Cys vs HI p = 0.382).…”

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confidence: 99%

Optimising the mutation screening strategy in Marfan syndrome and identifying genotypes with more severe aortic involvement

Stengl

Bors

Ágg

et al. 2020

Orphanet J Rare Dis

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“…Marfan's syndrome (MFS) is an autosomal dominant connective tissue disorder with cardiovascular involvement [56,57]. With a prevalence of around 1/3000 to 1/5000 individuals, the cause of the disorder has been extensively linked to mutations in the pleiotropic FBN-1 gene, which encodes an extracellular matrix protein (ECM), fibrillin-1 [58].…”

Section: Marfan's Syndromementioning

confidence: 99%

Disorders of the Aorta and Aortic Valve in Connective Tissue Diseases

et al. 2020

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Purpose of Review The incidence of aortic valve disease in inherited connective tissue disorders is well documented; however, recent studies have only begun to unravel the pathology behind this association. In this review, we aim to describe the etiology, clinical manifestations, management, and prognosis of aortic and aortic valvular disorders that co-exist in a variety of connective tissue diseases. An extensive literature review was performed in PubMed. Articles from 2008 to 2018 were included for review. Predetermined search terms used in PubMed include "aortic manifestation of connective tissue diseases" and "aortic valve disorders in rheumatologic disease." Recent Findings Manifestations of aortic valve disease in the context of connective tissue disorders include valvular stenosis, regurgitation, and/or thoracic aortic aneurysms. Both inherited and inflammatory connective tissue disorders contribute to aortic valve damage with increased susceptibility associated with specific gene variants. Summary Anti-inflammatory and immunosuppressive therapies have demonstrated beneficial results in Marfan's syndrome, Behcet disease, rheumatoid arthritis, ankylosing spondylitis, and systemic sclerosis, often leading to remission. Yet, such therapy is less effective in other disorders compared to alternative treatments such as surgical intervention. Additionally, regular echocardiographic studies should be recommended to those suffering from these disorders, especially those at higher risk for cardiovascular involvement. Given the rates of relapse with immunosuppressants, even following aortic valve replacement, further studies are needed to determine if certain dosing and/or combinations of immunosuppressants could be given to those diagnosed with connective tissue diseases to prevent progression of aortic valve involvement.

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“…The international database lists 1847 unique variants in FBN1 (http://www.umd.be/FBN1/) 24 . Mutations in FBN1 range from single base substitutions to large genomic deletions or duplications 25,26,27,28 . Only 1.7% of the records in the database show large deletions or duplications (≥ 1 exon), whereas In our laboratory, 12% of the pathogenic mutations are large deletions or duplications.…”

Section: Variants In Fbn1 and Their Interpretationmentioning

confidence: 99%

Marfan Syndrome, A Review

Pals

2018

J. Biomed. Transl. Res.

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Marfan syndrome is named after the French pediatrician Antoine Bernard-Jean Marfan who described in 1896 a girl with arachnodactyly and long limbs1. The patient also had congenital contractures of the elbows and would not fulfill the current criteria for Marfan syndrome. She probably was suffering from a condition that we now call contractural arachnodactyly, caused by mutations in the FBN2 gene.The clinical features of Marfan syndrome affect many systems of the body. The most obvious are the skeletal features, long limbs, tall stature, long thin fingers (arachnodactyly or spider fingers). The skeletal features can be scored objectively as: arm span more than 1.05 x body length; wrist sign (thumb and index finger can encircle the wrist of the other hand with at least one digit overlap) and thumb sign (when making a fist around the thumb, one digit of the thumb sticks out). The main neurological symptom is dural ectasias. The most severe symptoms are cardiovascular: mitralis valve prolapse, aortic dilatation and thoracic aortic aneurysms and dissections, which may lead to sudden death5. However, I noticed in discussions with patients that they often consider the ocular symptoms, severe myopia and lens luxation, the worst for themselves, because the latter may lead to blindness.

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Identification of gross deletions in FBN1 gene by MLPA

Cited by 16 publications

References 16 publications

Optimising the mutation screening strategy in Marfan syndrome and identifying genotypes with more severe aortic involvement

Optimising the mutation screening strategy in Marfan syndrome and identifying genotypes with more severe aortic involvement

Disorders of the Aorta and Aortic Valve in Connective Tissue Diseases

Marfan Syndrome, A Review

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