ARAP3 and Lymphatic Malformation

In recent studies, rare heterozygous missense variants in ARAP3 have been identified in patients with lymphatic malformation, a developmental disorder of the lymphatic vessels (PMID:32908855). These studies screened large cohorts where most patients were negative for mutations in known lymphedema‐associated genes, prompting the evaluation of ARAP3 as a novel candidate.

The initial case report evaluated a cohort of 235 Italian patients with lymphatic malformations and detected ARAP3 rare missense variants in three probands (PMID:32908855). Although family segregation analysis in two of these families did not reveal additional affected relatives, the observation of these variants in unrelated cases supports a potential gene–disease link.

A subsequent multi‐patient study using a next-generation sequencing panel in 408 individuals with primary lymphedema further reported ARAP3 among a set of genes harboring variants in the PI3K/AKT pathway (PMID:39207407). This independent evidence reinforces the role of ARAP3 in lymphatic vascular perturbations even though the contribution of each gene varied across the panel.

Complementing the clinical data, functional assessment studies using animal models have demonstrated that ARAP3 is down-regulated in murine lymphatic vessels. Experimental data from mouse and zebrafish models indicate that ARAP3 is critical for lymphatic vascular development, where its dysregulation disrupts normal lymphangiogenesis (PMID:24163130).

Together, the genetic findings of rare heterozygous missense variants – exemplified by the variant c.123A>T (p.Lys41Asn) – and the supportive functional experiments suggest that ARAP3 contributes to the pathogenesis of lymphatic malformation, even in the setting of limited segregation evidence. The combined data support a mechanism involving impaired modulation of cell adhesion and migration during lymphatic vessel organogenesis.

In summary, while segregation data remain sparse, the integration of multiple independent genetic observations with robust experimental validation indicates a moderate association between ARAP3 and lymphatic malformation. This association underscores the gene’s potential utility in diagnostic screening for patients with lymphatic developmental disorders.

Key Take‑home Sentence: ARAP3 is a promising candidate for inclusion in genetic testing panels for lymphatic malformation, facilitating improved diagnostic precision.

References

• International journal of genomics • 2020 • Mutations in the ARAP3 Gene in Three Families with Primary Lymphedema Negative for Mutations in Known Lymphedema-Associated Genes PMID:32908855
• Lymphology • 2023 • Genetic Variants in Genes Correlated to the PI3K/AKT Pathway: The Role of ARAP3, CDH5, KIF11 and RELN in Primary Lymphedema PMID:39207407
• Human molecular genetics • 2014 • Arap3 is dysregulated in a mouse model of hypotrichosis-lymphedema-telangiectasia and regulates lymphatic vascular development PMID:24163130

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