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Clinical and genetic screening in a large Iranian family with Marfan syndrome: A case study
Farzane Vafaeie1, Zahra Miri Karam2,3, Abolfazl Yari1,3
1Cellular and Molecular Research Center Birjand University of Medical Sciences Birjand Iran.
Background And Aims:
Marfan syndrome (MFS) is an autosomal dominant genetic disorder caused by pathogenic variants of the fibrillin-1-encoding FBN1 gene that commonly affects the cardiovascular, skeletal, and ocular systems. This study aimed to evaluate the clinical features and genetic causes of the MFS phenotype in a large Iranian family.
Methods:
Seventeen affected family members were examined clinically by cardiologists and ophthalmologists. The proband, a 48-year-old woman with obvious signs of MFS, her DNA sample subjected to whole-exome sequencing (WES). The candidate variant was validated by bidirectional sequencing of proband and other available family members. In silico analysis and molecular modeling were conducted to determine the pathogenic effects of the candidate variants.
Results:
The most frequent cardiac complications are mitral valve prolapse and regurgitation. Ophthalmic examination revealed iridodonesis and ectopic lentis. A heterozygous missense variant (c.2179T>C/p.C727R) in exon 19 of FBN1 gene was identified and found to cosegregate with affected family members. Its pathogenicity has been predicted using several in silico predictive algorithms. Molecular docking analysis indicated that the variant might affect the binding affinity between FBN1 and LTBP1 proteins by impairing disulfide bond formation.
Conclusion:
Our report expands the spectrum of the Marfan phenotype by providing details of its clinical manifestations and disease-associated molecular changes. It also highlights the value of WES in genetic diagnosis and contributes to genetic counseling in families with MFS.
Insights
Marfan syndrome (MFS) is a genetic disorder affecting multiple systems. A novel FBN1 gene variant was identified in an Iranian family, impacting protein interactions and aiding genetic diagnosis.
Area of Science:
- Genetics
- Molecular Biology
- Medical Science
Background:
- Marfan syndrome (MFS) is an autosomal dominant genetic disorder.
- Caused by pathogenic variants in the fibrillin-1-encoding FBN1 gene.
- Primarily affects cardiovascular, skeletal, and ocular systems.
Purpose of the Study:
- Evaluate clinical features of MFS in a large Iranian family.
- Identify genetic causes of the MFS phenotype.
- Characterize the molecular basis of MFS in the studied cohort.
Main Methods:
- Clinical examination of 17 affected family members by cardiologists and ophthalmologists.
- Whole-exome sequencing (WES) of the proband.
- Validation of candidate variants by bidirectional sequencing and in silico analysis.
Main Results:
- Identified a heterozygous missense variant (c.2179T>C/p.C727R) in exon 19 of the FBN1 gene.
- The variant cosegregated with affected individuals in the family.
- In silico analysis suggested the variant impairs FBN1-LTBP1 protein binding by affecting disulfide bond formation.
Conclusions:
- Expands the spectrum of Marfan syndrome phenotypes and associated molecular changes.
- Highlights the utility of whole-exome sequencing for MFS genetic diagnosis.
- Contributes to genetic counseling for families affected by Marfan syndrome.
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