Mosaicism in Marfan Syndrome: Clinical Implications and Variant Allele Frequency Interpretation in a Narrative Review

Marfan syndrome (MFS) is an autosomal dominant disorder of the connective tissue caused by pathogenic variants in the FBN1 gene, characterized by cardiovascular, ocular, and skeletal involvement. Although some of these cases are considered sporadic, recent advances in next-generation sequencing (NGS) have revealed that certain cases might be attributable to parental mosaicism. Mosaicism, defined as the presence of genetically distinct cell populations arising from postzygotic mutations, retains important implications in diagnosis, phenotypic variability, recurrence risk, and genetic counseling. However, the interpretation of variant allele frequency (VAF) remains challenging and lacks standardization. This narrative review summarizes our current knowledge on mosaicism in MFS, with a focus on VAF interpretation and its clinical implications. We performed a literature search using PubMed, focusing on studies published between 2010 and 2025, including relevant original and review articles addressing mosaicism in MFS. Although VAF serves as a quantitative indicator of mosaicism, its interpretation is influenced by tissue distribution, mutation timing, and sequencing methodology. Peripheral blood VAF does not necessarily reflect variant burden in clinically relevant tissues, limiting its utility in predicting disease severity. Advances in high-sensitivity techniques, including NGS and digital droplet PCR, have improved the detection of low-level mosaicism, although multi-tissue analysis might be required for accurate diagnosis. Mosaicism is an underrecognized but clinically important factor in MFS, particularly in apparently sporadic cases or when genotype-phenotype discordance is observed. Failure to detect mosaic variants may result in underestimation of disease severity, inaccurate risk assessment, and suboptimal genetic counseling. Clinicians should therefore consider mosaicism in atypical presentations, utilize high-sensitivity sequencing methods when appropriate, and assess parental status to refine recurrence risk. However, interpretation of VAF remains challenging due to tissue variability and methodological differences, and standardized frameworks linking VAF to clinical outcomes are lacking.