Marfan syndrome is caused by heterozygous pathogenic variants in FBN1, which encodes fibrillin-1, a glycoprotein essential for extracellular matrix integrity and connective tissue structure. ClinGen has assigned DEFINITIVE classification to FBN1 as the causative gene. As described in GeneReviews, few definitive genotype-phenotype correlations exist in FBN1-related Marfan syndrome; none is absolute. As a general principle documented in GeneReviews, variants that produce in-frame loss or gain of cysteine residues in EGF-like domains have been noted in association with more severe cardiovascular manifestations, though this correlation is not consistent across cases. ClinVar records 1 pathogenic variant for this condition. The condition demonstrates high clinical penetrance according to GeneReviews, with intrafamilial clinical expression variability that can be extensive. A single heterozygous FBN1 pathogenic variant is sufficient to produce the disorder.

According to GeneReviews, consensus clinical diagnostic criteria for FBN1-related Marfan syndrome have been published. The diagnosis is considered in individuals presenting with characteristic skeletal, cardiovascular, and ocular features. The revised Ghent nosology represents the primary published diagnostic framework, incorporating a scoring system that weights major and minor findings across organ systems alongside results from FBN1 molecular testing. Molecular genetic testing of FBN1 is central to diagnostic confirmation, identifying pathogenic or likely-pathogenic variants. Echocardiography to evaluate aortic root diameter and slit-lamp ophthalmologic examination for ectopia lentis are key components of the diagnostic evaluation documented in GeneReviews. The differential diagnosis documented in GeneReviews includes Loeys-Dietz syndrome, which shares features such as aortic involvement and skeletal findings but is caused by pathogenic variants in distinct genes and may carry a different cardiovascular risk profile.

Management of Marfan syndrome is most effectively accomplished through a multidisciplinary team of specialists that includes clinical genetics, cardiology, and ophthalmology, as described in GeneReviews. Documented foundational approaches in this packet include beta-blocker therapy — specifically atenolol or propranolol — directed at reducing aortic wall stress, and losartan as an alternative or adjunct agent for aortic protection. Annual echocardiographic monitoring of aortic root diameter forms a core component of surveillance protocols described in GeneReviews. Prophylactic aortic root surgery is performed when the aortic diameter reaches a specified clinical threshold. Ophthalmologic monitoring and management of lens dislocation are integral components of care. GeneReviews documents that contact sports, competitive sports, and isometric exercise are among circumstances associated with elevated cardiovascular risk; aerobic activities are not excluded and individuals are documented as able to remain physically active in appropriate exercise forms. No FDA-approved drugs are listed in this packet's approved treatments field; the approaches described are management and monitoring strategies drawn from GeneReviews and the packet's foundational therapy records.

The clinical course of Marfan syndrome is shaped primarily by cardiovascular involvement, particularly the trajectory of aortic root dilatation over time. No structured natural history data are present in this packet's natural history field. GeneReviews describes a broad phenotypic continuum with considerable variation in disease severity across affected individuals. The most significant life-threatening complication is aortic dissection or rupture, the risk of which is substantially influenced by surveillance protocols and prophylactic surgical intervention when diameter thresholds are reached. Neonatal Marfan syndrome, the recognized disease subtype in this dataset, is associated with a more severe and earlier-onset clinical presentation. GeneReviews notes that FBN1-related Marfan syndrome shows high clinical penetrance, and the extent of clinical expression can vary substantially even among members of the same family.

Ten clinical trials related to Marfan syndrome are recorded in ClinicalTrials.gov data within this packet. Active investigations include a transcriptomic study of adult populations with Marfan syndrome (NCT05700175, active not recruiting) and a national network study for cardiovascular genomics in hereditary cardiovascular diseases (NCT06546137). A study examining aortic dissection in the context of pregnancy in Marfan syndrome is in active recruitment (NCT07672210). GeneReviews directs reference to ClinicalTrials.gov and the EU Clinical Trials Register for current clinical research enrollment information. Research areas in this condition include FBN1 genotype-phenotype correlations, thresholds for prophylactic aortic surgical intervention, and pharmacologic strategies for aortic wall protection. The DEFINITIVE ClinGen classification of FBN1 provides a firm molecular foundation for ongoing translational and genetic research.