Genetic Variants in <i>LZTR1, MAP2K1</i> and <i>RAF1</i>: Insights into the Role of RAS-MAPK Pathway in Primary Lymphedema.

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 <i>LZTR1, RAF1</i> and <i>MAP2K1</i>. 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 <i>RAF1</i> (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.