Double somatic mosaicism in Marfan syndrome

Area of Science:

• Genetics
• Molecular Biology
• Medical Genetics

Background:

• Marfan syndrome (MFS) is a genetic connective tissue disorder caused by FBN1 gene variants.
• It affects cardiovascular, ocular, and skeletal systems, diagnosed via the Ghent nosology.
• Clinical variability is a hallmark of MFS.

Observation:

• A child diagnosed with Marfan syndrome presented with a systemic score of 9.
• Genetic analysis revealed two pathogenic mosaic frameshift variants in the FBN1 gene.
• These variants were detected in both ectodermal and mesodermal tissues, indicating an early developmental mutation.

Findings:

• This is the first reported case of Marfan syndrome with two pathogenic mosaic variants in the FBN1 gene.
• The presence of mosaicism in multiple tissue types suggests a mutation event occurring before gastrulation.
• A proposed mechanism involves defective repair of a de novo variant on the complementary DNA strand.

Implications:

• This case expands the understanding of genetic mechanisms underlying Marfan syndrome.
• It highlights the importance of considering mosaicism in genetic diagnoses, even in rare presentations.
• Further research into mosaic variant repair mechanisms may offer new diagnostic or therapeutic insights.