What is the management approach for a patient with variants of uncertain significance in the FBN1, FBN2, and LTBP4 genes?

Management Approach for Variants of Uncertain Significance in FBN1, FBN2, and LTBP4 Genes

Patients with variants of uncertain significance (VUS) in FBN1, FBN2, and LTBP4 genes should undergo comprehensive cardiovascular evaluation including echocardiography and clinical assessment for Marfan syndrome features, regardless of the uncertain genetic status. 1

Understanding Variants of Uncertain Significance

• VUS represent genetic alterations where there is insufficient evidence to classify them as either pathogenic or benign 1
• The FBN1 gene is associated with Marfan syndrome, an autosomal dominant connective tissue disorder that can lead to aortic dilatation, dissection, and rupture 1
• FBN2 variants are associated with congenital contractural arachnodactyly and other connective tissue disorders 1
• LTBP4 variants have been linked to cutis laxa and connective tissue disorders 1

Clinical Evaluation Approach

Initial Assessment

• Perform thorough cardiovascular evaluation with echocardiography to assess for aortic root dilatation, mitral valve prolapse, and other cardiac manifestations 1
• Evaluate for skeletal manifestations (arachnodactyly, dolichostenomelia, pectus deformities) 1
• Conduct ophthalmologic examination to check for ectopia lentis and other ocular findings 1
• Document family history of aortic disease, sudden cardiac death, or connective tissue disorders 1

Imaging Recommendations

• Baseline echocardiography to measure aortic root dimensions 1
• Consider magnetic resonance imaging from cerebrovascular circulation to pelvis if clinical suspicion for connective tissue disorder is high 1
• Follow-up imaging frequency should be determined based on clinical findings rather than genetic status alone 1

Management Strategy Based on Clinical Findings

For Patients with No Clinical Features

• Baseline cardiovascular evaluation with echocardiography 1
• If normal, consider periodic cardiovascular monitoring (every 2-5 years) 1
• Counsel that VUS cannot be used for predictive testing in family members 1
• Explain that VUS may be reclassified in the future as more evidence becomes available 2

For Patients with Some Clinical Features

• More frequent cardiovascular monitoring (every 1-2 years) 1
• Consider activity restrictions based on clinical findings, not solely on genetic status 1
• In case of positive family history but uncertain phenotype, patients should undergo periodic cardiovascular monitoring 1

For Patients with Significant Clinical Features

• Management should follow guidelines for the suspected clinical syndrome regardless of VUS status 1
• Consider surgical intervention for aortic dilatation based on established clinical criteria, not genetic status alone 1
• Avoid strenuous physical activities if aortic dilatation is present 1

Genetic Counseling and Family Management

• Explain that VUS cannot be used for predictive testing in family members 1
• Consider testing affected family members to help reclassify the variant 1, 2
• Family segregation studies can provide valuable information for variant reclassification 1
• Recommend periodic reassessment of the variant classification as more data becomes available 2

Variant Reclassification Considerations

• Recent studies show that 62.3% of FBN1 VUS were reclassified as pathogenic or likely pathogenic upon reassessment using gene-specific guidelines 2
• Major causes of reclassification include gene-specific modification of criteria, updated literature, and additional genetic testing 2
• Consider requesting laboratory reassessment of variants every 1-2 years 2
• Gene-specific knowledge can significantly impact variant classification, especially for FBN1 3

Important Caveats

• Avoid making definitive diagnoses based solely on VUS findings 1
• Do not use VUS for predictive genetic testing in family members 1
• Be aware that classification of variants may change over time as more evidence accumulates 4, 2
• Recognize that males with FBN1 variants may have higher risk of aortic involvement regardless of variant classification 5
• Consider that variants in critical regions of FBN1 (especially cysteine residues) are more likely to be pathogenic 3