Table 1.

Genes and Phenotypes Associated with Symptomatic Lymphatic Disorders

Gene	Disease and Phenotype	Reference(s)
VEGFR3	Nonne-Milroy disease	(Butler et al., 2007; Butler et al., 2009; Ferrell et al., 1998; Irrthum et al., 2000; Karkkainen et al., 2000)
	Several heterozygous missense mutations impacting the tyrosine kinase activity of vascular endothelial growth factor receptor 3 (VEGFR3) are responsible for this disease, characterized by congenital bilateral lower limb lymphedema. Mutations in VEGFR3 are also responsible for the mutant mouse strain Chy with defective lymphatic vessels, chylous ascites and lymphedematous limb swelling after birth.
FOXC2	Lymphedema-distichiasis (LD) syndrome	(Brice et al., 2002; Dagenais et al., 2004; Falls and Kertesz, 1964; Fang et al., 2000; Finegold et al., 2001; Ghalamkarpour et al., 2009; Neel and Schull, 1954; Petrova et al., 2004; van Steensel et al., 2009)
	This autosomal dominant disorder is characterized by distichiasis (i.e., double row of eyelashes) at birth and bilateral lower limb lymphedema at puberty. The number of lymphatic vessels appears normal in patients with LD; however, they have impaired lymphatic drainage. This defect is likely a consequence of abnormal valve development/function and aberrant mural cell coating in the collecting lymphatic vessels of LD patients and Foxc2 mutant mice. The majority of FOXC2 mutations are insertions, deletions or nonsense mutations, leading to mRNA decay or truncated loss-of-function proteins.
SOX18	Hypotrichosis-lymphedema-telangiectasia (HLTS) syndrome	(Francois et al., 2008; Irrthum et al., 2003; Pennisi et al., 2000)
	A rare disease characterized by the absence of eyebrows and eyelashes, edema of the inferior members or eyelids, and peripheral vein anomalies. Ragged mice carrying point mutations in Sox18 are considered a model for HLTS. These mice exhibit defective vasculogenesis and folliculogenesis, as well as lymphatic vessel malformations, similar to those of humans with HLTS.
CCBE1	Hennekam lymphangiectasia-lymphedema syndrome type 1	(Alders et al., 2009; Alders et al., 2013; Bos et al., 2011; Bui et al., 2016; Connell et al., 2010; Hennekam et al., 1989; Jha et al., 2017; Van Balkom et al., 2002)
	This syndrome is caused by homozygous and compound heterozygous mutations in the extracellular collagen and calcium-binding EGF domain-1 protein (CCBE1) and is characterized by severe peripheral lymphedema associated with intestinal lymphangiectasias, characteristic facial features, growth and mental retardation and hydrops fetalis. CCBE1 is important to facilitate the proteolytic cleavage and activation of the major VEGFR3 ligand, VEGFC.
FAT4	Hennekam lymphangiectasia-lymphedema syndrome 2	(Alders et al., 2014, Betterman et al., 2020; Pujol et al., 2017)
	Homozygous and compound heterozygous mutations in FAT4, encoding the giant atypical cadherin FAT4 were identified in Hennekam syndrome patients in whom no CCBE1 mutations were found. FAT4 is important for coordinating LEC polarity in response to flow and as a result, regulates lymphatic vessel valve development.
ADAMTS3	Hennekam lymphangiectasia-lymphedema syndrome 3	(Brouillard et al., 2017; Jeltsch et al., 2014)
	This syndrome is caused by loss of activity of the protease a disintegrin and metalloproteinase with thrombospondin motifs 3 (ADAMTS3), a protease also required for the proteolytic cleavage and activation of VEGFC. In these patients, bi-allelic missense mutations in ADAMTS3 were identified.
FBXL7	Hennekam lymphangiectasia-lymphedema syndrome	(Boone et al., 2020)
	Is caused by a homozygous single-exon deletion affecting FBXL7 (F-Box and leucine rich repeat protein 7). Data suggests that FBXL7 may be the fourth gene for Hennekam syndrome acting via a shared pathway with FAT4.
GJC2	Late-onset autosomal dominant lymphedema	(Ferrell et al., 2010; Lyons et al., 2017; Ostergaard et al., 2011a)
	Missense mutations in GJC2 (gap junction protein gamma-2) were discovered in a few families with late-onset autosomal dominant lymphedema affecting all 4 extremities; although some families showed reduced penetrance. GJC2 is a key effector of venous valve development, though the precise role of GJC2 in lymphatic vessels remains enigmatic.
GATA2	Emberger syndrome	(Geng et al., 2016; Hahn et al., 2011; Kazenwadel et al., 2012; Kazenwadel et al., 2015; Ostergaard et al., 2011b)
	Heterozygous, loss of function mutations in GATA-binding protein 2 were identified in patients with primary lymphedema with myelodysplasia progressing to acute myeloid leukemia (Emberger syndrome). GATA2 is important for the development and maintenance of lymphovenous and lymphatic vessel valves.
PTPN14	Choanal atresia and lymphedema	(Au et al., 2010)
	An intragenic deletion encompassing both sides of exon 7 of PTPN14 (protein tyrosine phosphatase, non-receptor type 14), a protein that by coimmunoprecipitation was shown to interact with VEGFR3 upon activation by VEGFC, was identified in a consanguineous family with autosomal recessive choanal atresia and lymphedema.
KIF11	MCLMR	(Ostergaard et al., 2012)
	Heterozygous mutations in KIF11 (kinesin family member 11, a DNAinteracting protein encoding the kinesin motor protein EG5) causes MLCRD (microcephaly, lymphedema, chorioretinal dysplasia) and CDMMR (chorioretinal dysplasia, microcephaly and mental retardation), 2 allelic syndromes that have now been regrouped as MCLMR (microcephaly with or without chorioretinopathy, lymphedema, or mental retardation). The role of KIF11 in the lymphatic vasculature remains to be established.
ITGA9	Integrin-α9 (ITGA9) is mutated in primary lymphedema; missense mutations in this gene were reported in fetuses with congenital chylothorax. Similar to humans with this condition, Itga9-null mice exhibit chylothorax and die a few days after birth. Characterization of Itga9-conditional mutant embryos revealed that ITGA9 is required for proper lymphatic vessel valve morphogenesis.	(Bazigou et al., 2009; Huang et al., 2000; Ma et al., 2008)
REELIN	Congenital lymphedema and accumulation of chylous ascites has also been reported in patients with homozygous mutations in REELIN, which encodes an extracellular matrix protein guiding neuronal cell migration. At least three patients with such mutation exhibited persistent neonatal lymphedema and one has accumulation of chyle. Reelin deletion in mice has been demonstrated to result in impaired maturation of collecting lymphatic vessels, suggesting that collecting vessel dysfunction may underlie the lymphatic defects observed in patients.	(Hong et al., 2000; Lutter et al., 2012)
PIEZO1	Generalized lymphatic dysplasia (GLD)	(Fotiou et al., 2015; Nonomura et al., 2018)
	Homozygous and compound heterozygous mutations in PIEZO1 (a mechanically activated ion channel) lead to an autosomal recessive form of GLD, a rare form of primary lymphoedema characterized by uniform, widespread edema, with systemic involvement including intestinal and/or pulmonary lymphangiectasia, pleural effusions, chylothorax and/or pericardial effusions. PIEZO1 is important for lymphatic vessel valve development.
EPHB4	Lymphatic-related hydrops fetalis	(Martin-Almedina et al., 2016)
	Ephrin receptor B4 kinase–inactivating missense mutations were identified as responsible for autosomal dominant lymphatic-related hydrops fetalis. Hydrops fetalis is characterized by fluid accumulation in at least 2 fetal compartments. Most cases of hydrops fetalis are nonimmune in nature and approximately 15% are a consequence of a lymphatic abnormality. Functional inactivation of Ephb4 in mice results in defective lymphovenous valve formation and subcutaneous edema.
CALCRL	Hydrops fetalis with lymphatic dysplasia	(Mackie et al., 2018)
	Nonimmune hydrops fetalis (NIHF) was associated with a recessive, in frame deletion in the G protein-coupled receptor, Calcitonin Receptor-Like Receptor (hCALCRL).