Genetic Study of HGF-MET Signaling Pathway in Primary Lymphedema Patients: Supporting Evidence for Loss of Function Variants in HGF.

The lymphatic system is composed of lymphatic vessels that connect lymphatic organs and play a critical role in draining lymph fluid from the intracellular environment. Disruptions in this system can lead to defects in lymphatic development and lymphedema which is characterized by chronic inflammation and fluid accumulation in tissues, finally resulting in swelling, pain, and fibrosis. If caused by genetic variants, this condition is referred to as primary lymphedema. This study explores the genetic basis of primary lymphedema in an Italian cohort retrospectively analyzing sequencing data and focusing specifically on genes involved in the HGF/MET signaling pathway. This pathway is crucial for lymphangiogenesis and lymphatic function, but the involved genes miss a clear association with lymphedema in clinical practice. The analysis identified 8 variants in three key genes, namely HGF, MET, and CBL, among 8 unrelated patients. Seven of these variants have never been reported in literature as associated with lymphedema. We performed molecular modeling studies to evaluate the effect of the three identified missense variants in MET, supporting the pathogenicity of two of them. The identification of these variants supports the significance of alterations in HGF/MET signaling pathway as possible causes of primary lymphedema.