44. UMI-based expanded NGS panel in precision molecular diagnosis of vascular anomalies: Early results

Abstract

Purpose

To describe early results from a highly sensitive genetic panel to evaluate patients with largely mosaic vascular anomalies

Methods

This is a single-center study utilizing a 218 gene panel with unique molecular identifier (UMI) adapters and an average 1000X target coverage. DNA was obtained from fresh, frozen or paraffin-embedded tissue, blood, buccal brushes, or cells pelleted from fluid.

Results

24 patients were evaluated in a vascular anomalies center and 6 patients were evaluated by dermatology, genetics, or oncology. 23/30 patients (76.7%) had identified causal variants. 25 variants were described: 11 PIK3CA, 4 TEK, 2 GNAQ, 2 KRAS, 1 KDR, 1 CELSR1, 1 PTEN, 1 SUFU, 1 MAP2K1, and 1 MTOR. These variants were classified as 21 pathogenic, 1 likely pathogenic, and 3 variants of uncertain significance (VUS). Of the 11 variants in PIK3CA, the kinase domain substitution at p.His1047 was the most frequently observed (36.3%). Mean variant allele frequency (VAF) was 18.7%, with a minimum VAF of 1.9%, therefore most variants were consistent with somatic mosaicism. Variants in CELSR1 and SUFU were identified at VAFs suggestive of a germline origin in patients who were not known to have germline variants. 6 patients had an alteration of clinical management based on the findings.

Conclusions

This genetic panel is highly effective in identifying somatic and germline clinically significant variants in patients with vascular anomalies. The prevalence of causative variants is higher than reported in previous studies. Future directions include validation of this panel in additional specimen types to extend utility.