Mutations in the Gene in Three Families with Primary Lymphedema Negative for Mutations in Known Lymphedema-Associated Genes.

Background: ARAP3 is a small GTPase-activating protein regulator, which has important functions in lymphatic vessel organogenesis and modulation of cell adhesion and migration. Mutations in the gene are associated with impaired lymphatic vessel formation.

Objective: The aim of our study was to determine the genotypes of lymphedema patients in relation to variants in the gene in order to explore its role in the development of lymphedema.

Methods And Results: We applied next-generation sequencing to DNA samples of a cohort of 246 Italian patients with lymphatic malformations. When we tested probands for known lymphedema genes, 235 out of 246 were negative. Retrospectively, we tested the DNA of these 235 patients for new candidate lymphedema-associated genes, including . Three out of 235 probands proved to carry rare missense heterozygous variants in . In the case of two families, other family members were also tested and proved negative for the variant, besides being unaffected by lymphedema. According to analysis, alterations due to these variants have a significant impact on the overall structure and stability of the resulting proteins.

Conclusions: Based on our results, we propose that variants in could be included in genetic testing for lymphedema.