Somatic PIK3R1 variation as a cause of vascular malformations and overgrowth.
Publication/Presentation Date
10-1-2021
Abstract
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.
Volume
23
Issue
10
First Page
1882
Last Page
1888
ISSN
1530-0366
Published In/Presented At
Cottrell, C. E., Bender, N. R., Zimmermann, M. T., Heusel, J. W., Corliss, M., Evenson, M. J., Magrini, V., Corsmeier, D. J., Avenarius, M., Dudley, J. N., Johnston, J. J., Lindhurst, M. J., Vigh-Conrad, K., Davies, O. M. T., Coughlin, C. C., Frieden, I. J., Tollefson, M., Zaenglein, A. L., Ciliberto, H., Tosi, L. L., … Drolet, B. A. (2021). Somatic PIK3R1 variation as a cause of vascular malformations and overgrowth. Genetics in medicine : official journal of the American College of Medical Genetics, 23(10), 1882–1888. https://doi.org/10.1038/s41436-021-01211-z
Disciplines
Medicine and Health Sciences
PubMedID
34040190
Department(s)
Department of Medicine
Document Type
Article