Somatic PIK3R1 variation as a cause of vascular malformations and overgrowth

Catherine E Cottrell ,Carrie C Coughlin ,Jeffrey N Dudley ,Meagan Corliss ,Olivia M T Davies ,Leslie G Biesecker ,Laura L Tosi ,Heather Ciliberto ,Jennifer J Johnston ,Ilona J Frieden ,Robert K Semple ,Nicole R Bender ,Katinka A Vigh‐Conrad ,Megha M Tollefson ,Michael T Zimmermann ,Matthew R Avenarius ,Marjorie J Lindhurst ,Andrea L Zaenglein ,Michael Evenson ,Vincent Magrini ,Jonathan W Heusel ,Donald J Corsmeier ,Beth A Drolet

doi:10.1038/s41436-021-01211-z

Abstract

PurposeSomatic 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. MethodsAffected 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. ResultsThe 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. ConclusionSomatic 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.

Highlights

Vascular malformations and the overgrowth syndromes of which they are commonly a part constitute a heterogeneous group of congenital malformations that lead to significant morbidity and disfigurement
The Genomics and Pathology Services (GPS) at Washington University School of Medicine cohort consisted of five PIK3R1 variant–positive individuals ascertained from a total of 343 individuals assayed clinically for suspected disorders of somatic mosaicism, including but not limited to overgrowth and vascular malformation
The variants detected in vascular malformation and overgrowth occur in domains that are common to all PIK3R1 products (p85α, p55α, and p50α)

Summary

Introduction

Vascular malformations and the overgrowth syndromes of which they are commonly a part constitute a heterogeneous group of congenital malformations that lead to significant morbidity and disfigurement. PIP3 generation triggers activation of downstream effectors including PDK1 and AKT, which promote cell growth and survival.[6] Somatic mosaic activating variants in PIK3CA, encoding the p110α catalytic subunit of the PI3K heterodimer, have been well described in vascular malformations and overgrowth syndromes.[7] Among the regulatory subunits of PI3K, PIK3R1 encodes three distinct protein products (p85α, p55α and p50α), generated through alternative splicing. These products form obligate heterodimers with PIK3CA, stabilizing and inhibiting it in the basal state, while mediating its binding to activated receptor tyrosine kinases and its subsequent activation.[8] PIK3R1 negatively regulates the PI3K pathway by stabilizing the phosphatase PTEN, itself a tumor suppressor.[9]

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Conclusion