Improving genetic diagnostic yield in a large cohort of children with rare vascular anomalies or -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 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 , , , , or , 4 individuals with fast-flow lesions with variants in or , 1 individual with a variant and a mixed phenotype, and 2 individuals with 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.