Mutation screening of all 65 exons of the fibrillin-1 gene in 60 patients with Marfan syndrome: Report of 12 novel mutations

Marfan syndrome (MFS) is an autosomal dominant genetic disorder of the connective tissue, typically characteristic of cardiovascular manifestations, valve prolapse, left ventricle enlargement, and cardiac failure. Fibrillin-1 (FBN1) is the causative gene in the pathogenesis of MFS. Patients with different FBN1 mutations often present more considerable phenotypic variation. In the present study, three affected MFS pedigrees were collected for genetic analysis. Using next-generation sequencing (NGS) technologies, 3 novel frameshift pathogenic mutations which are cosegregated with affected subjects in 3 pedigrees were identified. These novel mutations provide important diagnostic and therapeutic insights for precision medicine in MFS, especially regarding the lethal cardiovascular events.

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Faculty Opinions recommendation of A nonsense mutation in the fibrillin-1 gene of a Marfan syndrome patient induces NMD and disrupts an exonic splicing enhancer.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1008392.105207 ◽

2002 ◽

Author(s):

Lynne Maquat

Keyword(s):

Marfan Syndrome ◽

Nonsense Mutation ◽

Syndrome Patient ◽

Exonic Splicing Enhancer ◽

Fibrillin 1 ◽

Splicing Enhancer

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Recurrent spontaneous coronary dissections in a patient with a de novo fibrillin-1 mutation without Marfan syndrome

Thrombosis and Haemostasis ◽

10.1160/th14-11-0913 ◽

2015 ◽

Vol 113 (03) ◽

pp. 668-670 ◽

Cited By ~ 2

Author(s):

Philipp von Hundelshausen ◽

Konrad Oexle ◽

Kiril Bidzhekov ◽

Martin Schmitt ◽

Michael Hristov ◽

...

Keyword(s):

Marfan Syndrome ◽

De Novo ◽

Fibrillin 1

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

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-020-01569-4 ◽

2020 ◽

Vol 15 (1) ◽

Author(s):

Roland Stengl ◽

András Bors ◽

Bence Ágg ◽

Miklós Pólos ◽

Gabor Matyas ◽

...

Keyword(s):

Marfan Syndrome ◽

Single Gene ◽

Mutation Screening ◽

Screening Method ◽

Connective Tissue Disorder ◽

Screening Strategy ◽

Gene Panel ◽

Dominant Negative ◽

Second Phase ◽

High Detection Rate

Abstract 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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Cardiomyopathy in Genetic Aortic Diseases

Frontiers in Pediatrics ◽

10.3389/fped.2021.682390 ◽

2021 ◽

Vol 9 ◽

Author(s):

Laura Muiño-Mosquera ◽

Julie De Backer

Keyword(s):

Marfan Syndrome ◽

Myocardial Dysfunction ◽

Genetic Defect ◽

Positive Family History ◽

Aortic Disease ◽

Aortic Aneurysms ◽

Aortic Diseases ◽

Pathogenic Variants ◽

Fibrillin 1

Genetic aortic diseases are a group of illnesses characterized by aortic aneurysms or dissection in the presence of an underlying genetic defect. They are part of the broader spectrum of heritable thoracic aortic disease, which also includes those cases of aortic aneurysm or dissection with a positive family history but in whom no genetic cause is identified. Aortic disease in these conditions is a major cause of mortality, justifying clinical and scientific emphasis on the aorta. Aortic valve disease and atrioventricular valve abnormalities are known as important additional manifestations that require careful follow-up and management. The archetype of genetic aortic disease is Marfan syndrome, caused by pathogenic variants in the Fibrillin-1 gene. Given the presence of fibrillin-1 microfibers in the myocardium, myocardial dysfunction and associated arrhythmia are conceivable and have been shown to contribute to morbidity and mortality in patients with Marfan syndrome. In this review, we will discuss data on myocardial disease from human studies as well as insights obtained from the study of mouse models of Marfan syndrome. We will elaborate on the various phenotypic presentations in childhood and in adults and on the topic of arrhythmia. We will also briefly discuss the limited data available on other genetic forms of aortic disease.

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