Improving genetic diagnostic yield in a large cohort of children with rare vascular anomalies or PIK3CA-related overgrowth spectrum

Purpose: Drugs that attenuate hyperactivation of the phosphatidylinositol 3-kinase-Akt and Ras-mitogen-activated protein kinase signaling pathways are emerging treatments for children with rare, intractable vascular anomalies or PIK3CA-related overgrowth spectrum (PROS) with an eligible genetic diagnosis. However, access to genetic testing remains a barrier to genetic diagnosis. Here, we implement a targeted molecular diagnostic strategy for vascular anomalies or PROS.

Methods: We applied a novel genetic testing strategy to children with vascular anomalies or PROS using a tiered approach of (1) droplet digital PCR, (2) Sanger sequencing, (3) high-depth exome sequencing, and (4) reanalysis of existing clinical exome data.

Results: We applied this strategy to 60 individuals detecting pathogenic somatic variants in 33 of 60 (55%). This included 26 individuals with slow-flow lesions with variants in PIK3CA, TEK, GNAQ, GNA11, BRAF, or PIK3R1, 4 individuals with fast-flow lesions with variants in KRAS or MAP2K1, 1 individual with a PIK3CA variant and a mixed phenotype, and 2 individuals with PIK3CA variants and PROS without vascular anomalies.

Conclusion: We demonstrate an effective genetic diagnostic strategy for children with vascular anomalies or PROS identifying somatic variants in 55% of individuals. Increasing genetic diagnostic yield extends the clinicogenetic spectrum and may provide access for those with intractable disease to therapeutic drug trials.