Hungarian Marfan family with large FBN1 deletion calls attention to copy number variation detection in the current NGS era

Bors

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.

Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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

Bors

et al. 2020

Orphanet J Rare Dis

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“…Other variants include nonsense and frameshift mutations leading to premature termination codon (PTC) as well as in-frame deletions/insertions and splicing-affecting intronic mutations [ 9 ]. Copy number variations (CNVs > 50 bp) and other structural variants can also be responsible for the disease [ 10 , 11 ]. Cysteine, of which more than 360 can be found in fibrillin-1, has a particularly important role in the tertiary structure of this protein through the formation of disulfide bridges [ 9 ].…”

Section: Genetic Background and Pathomechanismmentioning

confidence: 99%

Potential predictors of severe cardiovascular involvement in Marfan syndrome: the emphasized role of genotype–phenotype correlations in improving risk stratification—a literature review

Pólos

et al. 2021

Orphanet J Rare Dis

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Background Marfan syndrome (MFS) is a genetically determined systemic connective tissue disorder, caused by a mutation in the FBN1 gene. In MFS mainly the cardiovascular, musculoskeletal and ocular systems are affected. The most dangerous manifestation of MFS is aortic dissection, which needs to be prevented by a prophylactic aortic root replacement. Main body The indication criteria for the prophylactic procedure is currently based on aortic diameter, however aortic dissections below the threshold defined in the guidelines have been reported, highlighting the need for a more accurate risk stratification system to predict the occurrence of aortic complications. The aim of this review is to present the current knowledge on the possible predictors of severe cardiovascular manifestations in MFS patients, demonstrating the wide range of molecular and radiological differences between people with MFS and healthy individuals, and more importantly between MFS patients with and without advanced aortic manifestations. These differences originating from the underlying common molecular pathological processes can be assessed by laboratory (e.g. genetic testing) and imaging techniques to serve as biomarkers of severe aortic involvement. In this review we paid special attention to the rapidly expanding field of genotype–phenotype correlations for aortic features as by collecting and presenting the ever growing number of correlations, future perspectives for risk stratification can be outlined. Conclusions Data on promising biomarkers of severe aortic complications of MFS have been accumulating steadily. However, more unifying studies are required to further evaluate the applicability of the discussed predictors with the aim of improving the risk stratification and therefore the life expectancy and quality of life of MFS patients.

“…Marfan syndrome (MFS) is a relatively common genetically determined connective tissue disorder with a prevalence of about 2–3 per 10,000 individuals ( 1 ). A wide variety of mutations in the fibrillin-1 ( FBN1 ) gene can be found in the majority of MFS patients ( 2 , 3 ). The mutations in the FBN1 gene, through the failure of fibrillin-1, a constituent of elastic fibers and microfibrils, cause decreased elastin content and fragmentation of elastic fibers.…”

Section: Introductionmentioning

confidence: 99%

Case Report: Morphological Characterization and Long-Term Observation of Bilateral Sequential Internal Mammary Artery Aneurysms in a Patient With Confirmed FBN1 Mutation

Front. Cardiovasc. Med.

Szilveszter

et al. 2021

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Marfan syndrome (MFS) is a genetically determined connective tissue disorder that leads to ocular, skeletal, and severe cardiovascular involvement. High mortality of MFS is associated with aortic dissection and aneurysm characteristic to the syndrome. In MFS, only a few cases of peripheral arterial involvement have been reported so far, mostly without a genetically confirmed diagnosis. We report a 41-year-old MFS patient with a saccular pearl-string-like aneurysm on the right internal mammary artery (RIMA) and a single aneurysm on the left internal mammary artery (LIMA). To our knowledge this is the first reported case on internal mammary artery aneurysms with this special morphology and with follow-up and blood pressure control as primary therapeutic approach in a patient with genetically confirmed MFS. The aneurysms with the above described morphology first appeared as small aneurysms on a CT scan 6 years after a cardiac operation. Due to the lack of guidelines, based on the asymptomatic state of the patient, the increased tortuosity of the affected vessels and the history of prior cardiac surgery, we decided to closely monitor these aneurysms with blood pressure control and without carrying out any interventions. On the CT scans done 3, 11, 12, 17, and 32 months after identifying the aneurysms, no progression of these structures was detected. Our findings confirm the possibility of the occurrence of internal mammary artery aneurysms in patients with FBN1 mutation and we believe that monitoring these aneurysms with blood pressure management can be a suitable option in selected cases.