Understanding Mosaicism in Marfan Syndrome: Clinical Implications and Genetic Insights

Marfan syndrome (MFS) is a hereditary systemic connective tissue disorder characterized by significant clinical variability. While typically caused by heterozygous pathogenic variants in the FBN1 gene, a rarer phenomenon known as mosaicism can complicate both diagnosis and clinical presentation. Understanding how mosaic variants affect the cardiovascular, ocular, and skeletal systems is critical for accurate patient management.

What is Mosaicism in Marfan Syndrome?

In most cases of Marfan syndrome, a genetic mutation is present in every cell of the body. However, somatic mosaicism occurs when only a subset of the body’s cells carries the pathogenic variant in the FBN1 gene. This means the individual has two or more genetically different cell populations.

Recent research has highlighted different forms of this occurrence:

• Somatic Mosaicism: Pathogenic variants that appear in some tissues but not others. This is often identified during familial screening, where many affected individuals remain asymptomatic.
• Double Somatic Mosaicism: An extremely rare occurrence where a patient carries two different pathogenic mosaic variants in the FBN1 gene. One documented case involved a child with a Marfan systemic score of 9, where variants were found in both ectodermal (buccal swab) and mesodermal (leukocyte) tissues, suggesting the mutation occurred prior to gastrulation [1].

Clinical Implications: Symptomatic vs. Asymptomatic Patients

The clinical impact of FBN1 mosaicism varies widely. Historically, the literature has described mosaic individuals as primarily asymptomatic. However, newer evidence challenges this assumption.

Symptomatic Mosaicism

Studies have identified “sporadic mosaic probands” who display the classical features typically associated with Marfan syndrome despite having mosaic rather than constitutive variants [2]. This indicates that mosaicism does not automatically result in a milder phenotype.

The Risk for Asymptomatic Carriers

Because some mosaic individuals may not show immediate symptoms, there is a significant risk of underdiagnosis. Experts advise that apparently asymptomatic mosaic parents undergo complete clinical examinations and regular cardiovascular follow-up to monitor for potential complications [2].

Challenges in Diagnosis and Genetic Testing

Identifying mosaicism requires sophisticated diagnostic tools, as standard testing may overlook low-frequency variants.

The Role of Next-Generation Sequencing (NGS)

Next-generation sequencing (NGS) capture technology has proven essential in detecting mosaic pathogenic variants. For patients who exhibit typical MFS features but show no single-nucleotide pathogenic variants or exon deletions/duplications through standard tests, an NGS capture panel with adapted variant calling analysis is recommended [2].

Variant Interpretation

The interpretation of variant allele frequency is vital. In cases of double somatic mosaicism, researchers propose that a defective repair of a de novo variant in the complementary strand may be the mechanism that creates two different populations of mutant cells carrying adjacent variants [1].

Key Takeaways for Patients and Clinicians

• Variable Presentation: Mosaicism in the FBN1 gene can lead to either classical MFS symptoms or an asymptomatic state.
• Critical Monitoring: Asymptomatic mosaic carriers require regular cardiovascular screenings.
• Advanced Testing: When typical MFS is suspected but initial genetic tests are negative, adapted NGS capture panels should be utilized.
• Rare Complexities: Double somatic mosaicism is exceptionally rare but possible, potentially involving multiple tissue types.

Frequently Asked Questions

Can someone have Marfan syndrome if they are a mosaic?

Yes. While many mosaic individuals are asymptomatic, some “sporadic mosaic probands” exhibit classical Marfan syndrome features [2].

Why is it hard to detect mosaicism in the FBN1 gene?

Mosaicism is often underestimated in molecular diagnosis because the pathogenic variant is not present in all cells. This requires specific bioinformatics parameters and adapted variant calling in NGS analysis to be identified [2].

What tissues are typically tested for mosaicism?

Testing may involve cells derived from different embryonic layers, such as buccal swabs (ectodermal tissue) and leukocytes (mesodermal tissue) [1].