Genetic tests in lymphatic vascular malformations and lymphedema

Abstract

Syndromes with lymphatic malformations show phenotypic variability within the same entity, clinical features that overlap between different conditions and allelic as well as 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, 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.

Segregation Analysis of Rare NRP1 and NRP2 Variants in Families with Lymphedema

“…Lymphedema is a progressive disease caused by lymphatic system malformations and impaired lymph flow. A panel consisting of 29 known lymphedema genes is currently used for the genetic testing of patients [24] but only detects relevant variants in 25-30% of patients [35,36]. This highlights the need for new target genes to screen.…”

“…Genetic testing was performed on genomic DNA extracted from saliva or peripheral blood of probands, as previously described [23]. Briefly, a custom-made oligonucleotide probe library was designed to capture all coding exons and flanking exon/intron boundaries (±15 bp) of genes known to be associated with lymphedema [24]. We added the candidate genes NRP1 and NRP2 to our panel.…”

The Role of Interventional Radiologists in the Treatment of Congenital Lymphatic Malformations

“…Additionally, RASA1 mutations have been associated with capillary, arteriovenous, and LMs. 12 Vascular endothelial growth factor receptor-3 (VEGFR3), when activated by vascular endothelial growth factor C (VEGFC), is associated with lymphangiogenesis, and VEGFC overexpression has been demonstrated in Milroy's disease. 7 Additional implicated genes include Ang2, Lyve1, and Nrp2.…”

Indocyanine Green Lymphography, Lymphoscintigraphy, and Genetic Analysis in Nonsyndromic Primary Lymphedema: The Distal Dermal Backflow Grading System and the Print Sign

“…Research of mutations included coding regions and intron-exon junctions of 11 genes (FLT4, GJC2, VEGFC, FOXC2, SOX18, GATA2, CCBE1, FAT4, KIF11, CELSR1, and HGF) and was performed according to the "Next generation sequencing" method. 20,21 Nucleotide alterations and regions of interest with coverage below 10X were analyzed and confirmed by polymerase chain reaction coupled with Sanger sequencing.…”