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Genetic tests in lymphatic vascular malformations and lymphedema
  1. Sandro Michelini1,
  2. Stefano Paolacci2,
  3. Elena Manara2,
  4. Costantino Eretta3,
  5. Raul Mattassi4,
  6. Byung-Boong Lee5,
  7. Matteo Bertelli2
  1. 1 Department of Vascular Rehabilitation, San Giovanni Battista Hospital, Rome, Italy
  2. 2 Research Unit, MAGI Euregio, Bolzano, Italy
  3. 3 Department of Surgery, Sant’Andrea Hospital, La Spezia, Italy
  4. 4 Center for Vascular Malformations, ‘Stefan Belov’, Clinical Institute Humanitas ‘Mater Domini’, Castellanza (Varese), Italy
  5. 5 Center for the Lymphedema and Vascular Malformations, George Washington University, Washington, District of Columbia, USA
  1. Correspondence to Dr Stefano Paolacci, Magi Euregio, Bolzano 39100, Italy; stefano.paolacci{at}


Syndromes with lymphatic malformations show phenotypic variability within the same entity, clinical features that overlap between different conditions and allelic as well as locus heterogeneity. The aim of this review is to provide a comprehensive clinical genetic description of lymphatic malformations and the techniques used for their diagnosis, and to propose a flowchart for genetic testing. Literature and database searches were performed to find conditions characterised by lymphatic malformations or the predisposition to lymphedema after surgery, to identify the associated genes and to find the guidelines and genetic tests currently used for the molecular diagnosis of these disorders. This search allowed us to identify several syndromes with lymphatic malformations that are characterised by a great heterogeneity of phenotypes, alleles and loci, and a high frequency of sporadic cases, which may be associated with somatic mutations. For these disorders, we found many diagnostic tests, an absence of harmonic guidelines for molecular diagnosis and well-established clinical guidelines. Targeted sequencing is the preferred method for the molecular diagnosis of lymphatic malformations. These techniques are easy to implement and have a good diagnostic success rates. In addition, they are relatively inexpensive and permit parallel analysis of all known disease-associated genes. The targeted sequencing approach has improved the diagnostic process, giving patients access to better treatment and, potentially, to therapy personalised to their genetic profiles. These new techniques will also facilitate the prenatal and early postnatal diagnosis of congenital lymphatic conditions and the possibility of early intervention.

  • Lymphatic Vascular Malformation
  • Lymphedema
  • Genetic Test
  • Next Generation Sequencing
  • Somatic Variant

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  • SM and SP contributed equally.

  • Contributors SM and MB conceived the study; SM, SP and MB collected information; SP wrote the original draft; SM contributed to major revision of the manuscript; SM, SP, EM, CE, RM, BBL and MB reviewed and edited the text; MB supervised the work and is responsible and guarantor for the overall content.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.