Clinical and genetic screening in a large Iranian family with Marfan syndrome: A case study

Abstract

AbstractBackground and AimsMarfan 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.MethodsSeventeen 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.ResultsThe 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.ConclusionOur 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.