The Reclassification of a FBN1 Variant of Unknown Significance Associated With Marfan Syndrome Through Careful Clinical Correlation and Family-Based Evaluation.

Background

Fibrillin-1 (FBN1) is a major structural component of the extracellular matrix, providing strength and stability to tissues. Pathogenic variants lead to the development of FBN1-associated syndromes which comprise a broad host of phenotypes, and more commonly, Marfan syndrome (MFS). MFS is typically diagnosed in patients presenting with ectopia lentis, thoracic or aortic disease, and skeletal features, which may prompt genetic testing. Case Presentation: In this case report, we describe the reclassification of a newly identified heterozygous FBN1 variant, c.2686T > A, p.(Cys896Ser), to likely pathogenic in a Caucasian 21-year-old female patient presenting with abnormal anterior eye segment with superior bilateral ectopia lentis; joint pain affecting wrists, knees, and upper back; and mild thoracolumbar scoliosis. Identification of this variant led to cascade testing in the patient's 49-year-old mother which revealed the same FBN1 variant and an incidental finding of aortic dilatation, prompting standard management. Notably, the identification and reclassification of the variant led to early diagnosis and preventive management in the patient's mother, including cardiovascular monitoring and treatment. The segregation of the phenotype in both patient and mother, the family member testing, the variant's absence in control populations, and all in silico tools predicting pathogenicity led to the reclassification of this FBN1 variant to likely pathogenic.

Conclusion

We highlight the reclassification of a variant of unknown significance through careful clinical correlation and family-based evaluation. This reclassification led to a timely diagnosis and preventive management through cascade testing, demonstrating the real-world utility of genetic testing and cascade screening in connective tissue disorders.