Abstract
The lymphatic system, a complex physiological network of lymphatic organs and vessels, is essential for maintaining fluid homeostasis. Dysfunction of lymphatic system can lead to lymphedema, a pathology characterized by the accumulation of interstitial fluid in peripheral tissues. This study aimed to identify novel genetic variants in genes within the RAS/ MAPK pathway and assess their potential association with lymphedema onset. We conducted a retrospective analysis of the genetic and clinical data from 408 patients diagnosed with primary lymphedema. These patients were previously tested using a next-generation sequencing panel that included 28 diagnostic genes and 71 candidate genes. The analysis revealed five genetic variants in the genes LZTR1, RAF1 and MAP2K1. Among the identified variants, four of them have never been reported in the literature. In silico analysis and molecular modelling supported the possible pathogenicity of one missense variant in RAF1 (c.1344T>G; p.Ile448Met), which could affect protein activation by phosphorylation. The results of this study highlight the genes involved in the RAS/MAPK signaling pathway as potential diagnostic targets for primary lymphedema.Keywords: LZTR1, MAP2K1, primary lymphedema, RAF1, RAS/MAPK pathway
https://doi.org/10.2458/lymph.9754