Generation of a CRISPR/Cas9-corrected-hiPSC (NCCDFWi001-A-1) from a Marfan syndrome patient hiPSC with a heterozygous c.2613A>C variant in the fibrillin 1 (FBN1) gene

Introduction: Left ventricular non-compaction cardiomyopathy (LVNC) is a rare and unique cardiomyopathy. Its presentation can range from a benign phenotype to overt heart failure and sudden cardiac death. The genetics of LVNC are not completely understood and current genetic testing has a yield of about 30% in identifying a causative gene mutation. We present a series of patients with LVNC and fibrillin-1 (FBN1) gene mutations. Hypothesis: We hypothesize that FBN1 gene mutations can lead to LVNC by way of its role in the myocardial extracellular matrix during cardiac development. Methods: A retrospective review of all patients with LVNC at our institution was performed for purposes of another investigation. The process unexpectedly identified patients with LVNC and FBN1 gene mutations, as well as LVNC and Marfan syndrome. Results: Approximately 150 patients are followed in our clinic with LVNC. We screened this population and found 51 patients on medical therapy for reduced function. We retrospectively reviewed gene testing in these 51 patients, when available, and identified 5 patients (10%) with an FBN1 gene mutation. All 5 patients had a dilated LVNC phenotype and previous or current evidence of left ventricular dysfunction. Syndrome breakdown as follows: 3 with Marfan, 1 with Shprintzen-Goldberg, and 1 with no identifiable syndrome. Dilated cardiomyopathy/LVNC gene testing was performed in 3 patients; 2 had disease causing myosin heavy chain 7 gene defects and 1 had no defects. Conclusions: The role of FBN1 in the human myocardium is not completely understood but it is expressed in the developing fetal heart and is a component of the myocardial extracellular matrix. Although causation has not been proven by our report, it certainly raises interest in a mechanistic relationship between LVNC and FBN1 given the increased prevalence of Marfan syndrome and probable increased prevalence of FBN1 gene mutations in this cohort of LVNC patients in light of FBN1.

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Large genomic fibrillin-1 (FBN1) gene deletions provide evidence for true haploinsufficiency in Marfan syndrome

Human Genetics ◽

10.1007/s00439-007-0371-x ◽

2007 ◽

Vol 122 (1) ◽

pp. 23-32 ◽

Cited By ~ 58

Author(s):

Gábor Mátyás ◽

Sira Alonso ◽

Andrea Patrignani ◽

Myriam Marti ◽

Eliane Arnold ◽

...

Keyword(s):

Marfan Syndrome ◽

Gene Deletions ◽

Fbn1 Gene ◽

Fibrillin 1

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Reprogramming of a human induced pluripotent stem cell line from a Marfan syndrome patient harboring a heterozygous mutation of c.2939G > A in FBN1 gene

Stem Cell Research ◽

10.1016/j.scr.2021.102163 ◽

2021 ◽

Vol 51 ◽

pp. 102163

Author(s):

Zhiping Qin ◽

Liqiang Sun ◽

Xue Sun ◽

Xinxuan Gao ◽

Hang Su

Keyword(s):

Stem Cell ◽

Cell Line ◽

Marfan Syndrome ◽

Pluripotent Stem Cell ◽

Induced Pluripotent Stem Cell ◽

Heterozygous Mutation ◽

Syndrome Patient ◽

Stem Cell Line ◽

Fbn1 Gene ◽

Induced Pluripotent

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A Novel Heterozygous Intronic Mutation in the FBN1 Gene Contributes to FBN1 RNA Missplicing Events in the Marfan Syndrome

BioMed Research International ◽

10.1155/2018/3536495 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 6

Author(s):

Mario Torrado ◽

Emilia Maneiro ◽

Juan Pablo Trujillo-Quintero ◽

Arturo Evangelista ◽

Alexander T. Mikhailov ◽

...

Keyword(s):

Connective Tissue ◽

Marfan Syndrome ◽

Premature Termination Codon ◽

Connective Tissue Disorder ◽

Aortic Dilatation ◽

Functional Protein ◽

Fbn1 Gene ◽

Intronic Mutation ◽

Aortic Pathology ◽

Fibrillin 1

Marfan syndrome (MFS) is an autosomal dominantly inherited connective tissue disorder, mostly caused by mutations in the fibrillin-1 (FBN1) gene. We, by using targeted next-generation sequence analysis, identified a novel intronic FBN1 mutation (the c.2678-15C>A variant) in a MFS patient with aortic dilatation. The computational predictions showed that the heterozygous c.2678-15C>A intronic variant might influence the splicing process by differentially affecting canonical versus cryptic splice site utilization within intron 22 of the FBN1 gene. RT-PCR and Western blot analyses, using FBN1 minigenes transfected into HeLa and COS-7 cells, revealed that the c.2678-15C>A variant disrupts normal splicing of intron 22 leading to aberrant 13-nt intron 22 inclusion, frameshift, and premature termination codon. Collectively, the results strongly suggest that the c.2678-15C>A variant could lead to haploinsufficiency of the FBN1 functional protein and structural connective tissue fragility in MFS complicated by aorta dilation, a finding that further expands on the genetic basis of aortic pathology.

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Paternal fibrillin-1 mutation transmitted to an affected son with neonatal marfan syndrome: the importance of early recognition

Cardiology in the Young ◽

10.1017/s1047951113001029 ◽

2013 ◽

Vol 24 (4) ◽

pp. 735-738 ◽

Cited By ~ 3

Author(s):

Huda Elshershari ◽

Catharine Harris

Keyword(s):

Marfan Syndrome ◽

Early Recognition ◽

Molecular Genetic ◽

Cardiac Abnormality ◽

Genetic Studies ◽

Dysmorphic Features ◽

Fbn1 Gene ◽

Fibrillin 1 ◽

Aortic Root Dilatation ◽

Neonatal Marfan Syndrome

AbstractWe describe a case of neonatal Marfan syndrome diagnosed because of a family history, dysmorphic features, and cardiac abnormality. The echocardiogram showed aortic root dilatation. Molecular genetic studies showed a mutation in exon 31 of the FBN1 gene in the infant and father. The infant was treated with losartan, which significantly slowed the rate of enlargement of the aorta.

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Mutation screening of the fibrillin-1 (FBN1) gene in 76 unrelated patients with Marfan syndrome or Marfanoid features leads to the identification of 11 novel and three previously reported mutations

Human Mutation ◽

10.1002/humu.9075 ◽

2002 ◽

Vol 20 (5) ◽

pp. 406-407 ◽

Cited By ~ 33

Author(s):

Kathrin Rommel ◽

Matthias Karck ◽

Axel Haverich ◽

J�rg Schmidtke ◽

Mine Arslan-Kirchner

Keyword(s):

Marfan Syndrome ◽

Mutation Screening ◽

Fbn1 Gene ◽

Fibrillin 1

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Cysteine-to-arginine point mutation in a ‘hybrid’ eight-cysteine domain of FBN1: consequences for fibrillin aggregation and microfibril assembly

Journal of Cell Science ◽

10.1242/jcs.108.3.1317 ◽

1995 ◽

Vol 108 (3) ◽

pp. 1317-1323 ◽

Cited By ~ 1

Author(s):

C.M. Kielty ◽

T. Rantamaki ◽

A.H. Child ◽

C.A. Shuttleworth ◽

L. Peltonen

Keyword(s):

Connective Tissue ◽

Point Mutation ◽

Marfan Syndrome ◽

Connective Tissue Disease ◽

Cell Cultures ◽

Autosomal Dominant ◽

Gene Encoding ◽

Fbn1 Gene ◽

Microfibril Assembly ◽

Fibrillin 1

Mutations in the FBN1 gene encoding the microfibrillar glycoprotein fibrillin cause Marfan syndrome, a relatively common autosomal dominant connective tissue disease. Causative FBN1 mutations appear to be dispersed throughout the coding frame, and to date no predictable genotype: phenotype correlations have emerged. We have identified a point mutation within an eight-cysteine ‘hybrid’ motif of the fibrillin polypeptide which results in the substitution of an arginine for a cysteine, in a patient severely affected in the cardiovascular, skeletal and ocular systems. We have utilised cell cultures from various tissues of this patient to investigate the effects of this mutation on fibrillin expression and deposition, and the consequences in terms of microfibril assembly and organisation. We have established that there is no difference in the expression of normal and mutant alleles, and fibrillin synthesis, secretion and deposition are also normal. However, the rate of fibrillin aggregation is reduced and microfibrillar assemblies are both remarkably scarce and morphologically abnormal. These data clearly demonstrate that the mutated allele interferes with normal assembly, and strongly implicate this particular region of the fibrillin-1 molecule in stabilising microfibrillar assemblies.

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Overview of Marfan Syndrome: knowns and unknowns

Journal of Controversies in Biomedical Research ◽

10.15586/jcbmr.2015.10 ◽

2015 ◽

Vol 1 (1) ◽

pp. 51-66

Author(s):

Pratiek N Matkar ◽

Hao H Chen ◽

Howard Leong-Poi ◽

Krishna Kumar Singh

Keyword(s):

Marfan Syndrome ◽

Drug Targets ◽

Transforming Growth Factor ◽

Surgical Techniques ◽

Clinical Manifestations ◽

Gene Mutations ◽

Transforming Growth Factor Β ◽

The Body ◽

Fbn1 Gene ◽

Fibrillin 1

Marfan syndrome (MFS) is a relatively rare disease of the connective tissue that affects several organs of the body. Cardiovascular abnormalities such as aortic root dilatation and mitral valve prolapse are the two main life-threatening complications associated with MFS. The complete pathogenesis of MFS is yet unclear. However, fibrillin-1 (FBN1) gene mutations and mutations in the transforming growth factor-β (TGFβ) signaling pathway are the leading causes of this lethal disease. Detailed assessment based on several major and minor clinical manifestations has led to the evolution of different nosologies for MFS diagnoses with reliable accuracies. Nevertheless, heterogeneous disease advancement and overlapping clinical outcomes make MFS diagnosis challenging. Rapid strides in research and surgical avenues over the last two decades have improved the life expectancy and the quality of life of MFS patients remarkably. More specific diagnostic criteria have been established, novel therapeutic targets for pharmacotherapy have been identified and validated, and newer surgical techniques have been tested. Current research efforts are focusing on the identification of prognostic biomarkers, gene modifiers, drug targets, and surgical procedures. This review aims to provide a brief overview of these aspects associated with MFS.

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