Somatic PIK3R1 variation as a cause of vascular malformations and overgrowth

Purpose Somatic activating variants in the PI3K-AKT pathway cause vascular malformations with and without overgrowth. We previously reported an individual with capillary and lymphatic malformation harboring a pathogenic somatic variant in PIK3R1, which encodes three PI3K complex regulatory subunits. Here, we investigate PIK3R1 in a large cohort with vascular anomalies and identify an additional 16 individuals with somatic mosaic variants in PIK3R1. Methods Affected tissue from individuals with vascular lesions and overgrowth recruited from a multisite collaborative network was studied. Next-generation sequencing targeting coding regions of cell-signaling and cancer-associated genes was performed followed by assessment of variant pathogenicity. Results The phenotypic and variant spectrum associated with somatic variation in PIK3R1 is reported herein. Variants occurred in the inter-SH2 or N-terminal SH2 domains of all three PIK3R1 protein products. Phenotypic features overlapped those of the PIK3CA-related overgrowth spectrum (PROS). These overlapping features included mixed vascular malformations, sandal toe gap deformity with macrodactyly, lymphatic malformations, venous ectasias, and overgrowth of soft tissue or bone. Conclusion Somatic PIK3R1 variants sharing attributes with cancer-associated variants cause complex vascular malformations and overgrowth. The PIK3R1-associated phenotypic spectrum overlaps with PROS. These data extend understanding of the diverse phenotypic spectrum attributable to genetic variation in the PI3K-AKT pathway.

Automated summary

Somatic variants in the PIK3R1 gene, similar to cancer-associated variants, cause complex vascular malformations and overgrowth. The phenotypic spectrum associated with PIK3R1 overlaps with the PIK3CA-related overgrowth spectrum, including features like mixed vascular malformations, macrodactyly, lymphatic malformations, venous ectasias, and overgrowth of tissues or bones. This study expands our understanding of the diverse phenotypic spectrum caused by genetic variations in the PI3K-AKT pathway.