Genetic Variants in Genes Correlated to the PI3K/AKT Pathway: The Role of ARAP3, CDH5, KIF22 and RELN in Primary Lymphedema

Abstract

Genetic anomalies affecting lymphatic development and function can lead to lym- phatic dysfunction, which could manifest as lymphedema. Understanding the signaling pathways governing lymphatics function is crucial for developing targeted diagnostic and therapeutic interventions. This study aims to characterize genetic variants in genes involved in the PI3K/AKT signaling pathway, which plays a critical role in lymphangiogenesis. 408 patients diagnosed with primary lymphedema were sequenced using a next-generation se- quencing (NGS) gene panel composed of 28 diagnostic genes and 71 candidate genes. The analysis revealed six variants in genes RELN, ARAP3, CDH5, and KIF11. Five of these vari- ants have never been reported in the literature. All these genes have been correlated to lym- phatic activity and are involved in the PI3K/ AKT pathway. As the PI3K/AKT signaling pathway plays an essential role in lymphangio- genesis and lymphatic function, genetic vari- ants in genes correlated to this pathway could lead to lymphedema. Our findings underscore. the potential of the PI3K/AKT pathway in lymphedema pathogenesis, supporting the role of RELN, ARAP3, CDH5, and KIF11 as diag- nostic and therapeutic targets.