Two rare PROX1 variants in patients with lymphedema

Background The PROX1 gene is specifically expressed in a subpopulation of endothelial cells that, by budding and sprouting, give rise to the lymphatic system. It also plays a critical role in neurogenesis and during development of many organs, such as the eye lens, liver, and pancreas. Methods We used next‐generation sequencing (NGS) to sequence the DNA of a cohort of 246 Italian patients with lymphatic malformations. We first investigated 29 known disease‐causing genes: 235 of 246 patients tested negative and were then retested for a group of candidate genes, including PROX1, selected from a database of mouse models. The aim of the study was to define these patients’ genotypes and explore the role of the candidate gene PROX1 in lymphedema. Results Two of 235 probands were found to carry rare heterozygous missense variants in PROX1. In silico analysis of these variants—p.(Leu590His) and p.(Gly106Asp)—indicates that the overall protein structure was altered by changes in interactions between nearby residues, leading to functional protein defects. Conclusions Our results suggest that PROX1 is a new candidate gene for predisposition to lymphedema. Background: The PROX1 gene is a specific marker expressed in a subpopulation of endothelial cells that by budding and sprouting give rise to the murine lymphatic system. It plays a critical role in embryo development and functions as a key regulatory protein in neurogenesis and the development of many organs, including the lymphatic system. Methods and Results: We used NGS to sequence the DNA of a cohort of 246 Italian patients with lymphatic malformations. We first investigated 29 known disease‐causing genes: 235 of 246 patients tested negative and were then tested for a group of candidate genes, including PROX1, selected from a database of mouse models. The aim of the study was to define these patients’ genotypes and explore the role of the candidate gene PROX1 in lymphedema. Two of 235 probands were found to carry rare missense heterozygous variants in PROX1. In silico analysis suggested that the overall protein structure was somehow altered by changes in interactions between nearby residues, leading to functional protein defects. Conclusions: Our results suggest that PROX1 is a possible candidate for predisposition to lymphedema.