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 ARAP3 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 ARAP3 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 ARAP3. Three out of 235 probands proved to carry rare missense heterozygous variants in ARAP3. In the case of two families, other family members were also tested and proved negative for the ARAP3 variant, besides being unaffected by lymphedema. According to in silico 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 ARAP3 could be included in genetic testing for lymphedema.

中文翻译：

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三个原发性淋巴水肿家族的 ARAP3 基因突变对已知淋巴水肿相关基因的突变呈阴性。

背景。ARAP3 是一种小型 GTPase 激活蛋白调节剂，在淋巴管器官发生和细胞粘附和迁移的调节中具有重要作用。ARAP3基因的突变与淋巴管形成受损有关。客观。我们研究的目的是确定与ARAP3基因变异相关的淋巴水肿患者的基因型，以探索其在淋巴水肿发展中的作用。方法和结果. 我们对 246 名意大利淋巴畸形患者的 DNA 样本进行了新一代测序。当我们检测已知淋巴水肿基因的先证者时，246 人中有 235 人为阴性。回顾性地，我们测试了这 235 名患者的 DNA 中是否存在新的候选淋巴水肿相关基因，包括ARAP3。235 名先证者中有 3 名被证明在ARAP3中携带罕见的错义杂合变体。在两个家庭的情况下，除了不受淋巴水肿影响外，其他家庭成员也接受了检测，并证明ARAP3变体呈阴性。根据计算机分析，由这些变体引起的改变对所得蛋白质的整体结构和稳定性有重大影响。结论。根据我们的结果，我们建议ARAP3中的变体可以包括在淋巴水肿的基因检测中。