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Disparities in Clinical Genetic Testing of Patients with Vascular Malformations: A Single Site Experience

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical Genetics
  • Secondary Categories:
    • Clinical Genetics
Introduction:
Genotyping in patients with lymphatic, arteriovenous, and venous malformations and/or somatic overgrowth is critical for guiding precision treatment and is often required for insurance approval of targeted medications. Due to low variant allele fraction (VAF), the recommended testing approach involves specialized genetic sequencing with a high depth of coverage (DOC) on a biopsy of affected tissue. Although guidelines for genetic testing in this population are well-established, uniform implementation in the clinical setting is hindered by practical challenges including logistical, insurance, and technical limitations. In our institution, access to specialty testing is primarily limited by insurance coverage, as our state public health insurance program (Medicaid) is not accepted by out-of-state academic laboratories. This study aims to compare the molecular diagnostic yield of genetic testing in vascular malformations between different specimen types, DOC, and billing methods to provide patients with realistic expectations for diagnosis.

Methods:
We conducted a retrospective chart review of patients who had genetic testing on a biopsy for vascular malformations and/or somatic overgrowth. Some individuals underwent multiple genetic tests, either on the same biopsy specimen or a new one. Genetic testing was performed at various commercial or academic CLIA-certified laboratories at the discretion of the ordering clinician, with most tests including a panel of overgrowth-related genes. Rarely, whole exome sequencing or somatic tumor panels were ordered. Diagnostic yield was compared by specimen type (core biopsy of affected tissue or skin punch biopsy), DOC (with "deep" defined as ≥1000x coverage), and billing method (Medicaid vs. private insurance, including institutional billing). Core biopsies comprised both ultrasound-guided needle core biopsies and tissue obtained during surgical excision. Results were considered positive if a pathogenic or likely pathogenic variant was identified that was concordant with the patient’s phenotype. 

Results:
70 genetic tests were reviewed for 56 patients with vascular malformation(s) and/or somatic overgrowth. Testing with deep DOC across all specimen types yielded a significantly higher diagnostic rate of 74.3% compared to 20.0% in low DOC testing (p < 0.001). Core biopsy testing achieved a diagnostic yield of 71.4%, while skin biopsy testing showed a yield of 22.9% (p < 0.001). Tests billed through Medicaid had a significantly lower diagnostic rate, with 24.0% positivity compared to 60.0% for those billed through private insurance or institutionally (p < 0.05). Molecular diagnoses included somatic pathogenic variants in PI3K/AKT/mTOR or Ras-MAPK-associated genes such as PIK3CA, TEK, and RASA1. Notably, no immediate complications were reported for patients who underwent ultrasound-guided needle core biopsy.

Conclusion:
In the clinical setting of a vascular anomalies center with limited access to specialty genetic testing, patients reliant on low DOC commercial testing due to insurance barriers face significantly lower diagnostic rates. Diagnostic yield is also lower among those who undergo skin rather than core biopsies; however, this trend may partly reflect DOC differences, as labs offering low DOC testing typically do not accept core biopsies. Core biopsies, especially when collected during sclerotherapy, present a viable diagnostic specimen if they are sent to a specialty laboratory adept at extracting DNA from small tissue samples. The inability of many patients to access deeper DOC testing and/or core biopsy due to logistical and insurance barriers underscores a clear inequity in diagnostic outcomes and the availability of precision treatment, particularly for patients reliant on Medicaid in our state. 

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