TY - JOUR
T1 - Somatic PIK3R1 variation as a cause of vascular malformations and overgrowth
AU - Cottrell, Catherine E.
AU - Bender, Nicole R.
AU - Zimmermann, Michael T.
AU - Heusel, Jonathan W.
AU - Corliss, Meagan
AU - Evenson, Michael J.
AU - Magrini, Vincent
AU - Corsmeier, Donald J.
AU - Avenarius, Matthew
AU - Dudley, Jeffrey N.
AU - Johnston, Jennifer J.
AU - Lindhurst, Marjorie J.
AU - Vigh-Conrad, Katinka
AU - Davies, Olivia M.T.
AU - Coughlin, Carrie C.
AU - Frieden, Ilona J.
AU - Tollefson, Megha
AU - Zaenglein, Andrea L.
AU - Ciliberto, Heather
AU - Tosi, Laura L.
AU - Semple, Robert K.
AU - Biesecker, Leslie G.
AU - Drolet, Beth A.
N1 - Funding Information:
L.G.B. has received in-kind research support from ArQule, Inc. (now wholly owned by Merck, Inc.), Novartis, and Pfizer Inc., royalties from Genentech, Inc, and honoraria from Cold Spring Harbor Press, as well as the following: Illumina Corp, Ethics Advisory Board. J.W.H. PierianDx, Knowledgebase Expert Panel member. B.A.D. has received in-kind research support from Venthera and research support for an investigator-initiated retrospective on oral propranolol from Pierre Fabre, and also reports the following: Venthera, Clinical Advisory Board; Consultant, Co-founder Pediatric Derm development, LLC. R.K.S. has received in-kind research support from Pfizer, Inc., and is a consultant for Novartis. L.L.T. has received research support from Ultragenyx Pharmaceutical. I.J.F. reports the following: Venthera, Consultant, Novartis, Consultant and Medical Advisory Board, Pfizer Inc., Data Safety Monitoring Boards. M.T. is a site principal investigator for Venthera. The other authors declare no competing interests.
Funding Information:
The authors thank the participating individuals and their families described in this manuscript for their support and cooperation and the NIH Intramural Sequencing Center for performing NGS capture and sequencing. L.G.B. was supported by the intramural research program of the National Human Genome Research Institute, grants HG200328 and HG200388. R.K.S. was supported by the Wellcome Trust, grant 210752/Z/18/Z.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/10
Y1 - 2021/10
N2 - 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.
AB - 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.
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U2 - 10.1038/s41436-021-01211-z
DO - 10.1038/s41436-021-01211-z
M3 - Article
C2 - 34040190
AN - SCOPUS:85106493295
VL - 23
SP - 1882
EP - 1888
JO - Genetics in Medicine
JF - Genetics in Medicine
SN - 1098-3600
IS - 10
ER -