Table 1.
Mutations associated with primary lymphedema
| Condition | Gene | Effect of Mutation | Inheritance |
|---|---|---|---|
| Capillary malformation | PIK3CA | Activating missense causing constitutively active PI3K-AKT signaling | Somatic |
| Choanal atresia/lymphedema syndrome | PTPN14 | Loss of function frameshift nonsense in the protein tyrosine phosphatase that inhibits VEGFR3 | Autosomal recessive |
| Cholestasis-lymphedema syndrome (Aagenaes syndrome) | CCBE1 | Loss of function causing decreased activation of the VEGF-C ligand | Autosomal recessive |
| CLOVES syndrome | PIK3CA | Activating missense resulting in constitutively active PI3K-AKT signaling | Somatic |
| CM-AVM/lymphedema |
EPHB4
RASA1 |
Inactivating heterozygous missense in the tyrosine kinase domain of EPHB4 Loss of function in the RAS GTPase-activating protein upregulating RAS/MAPK signaling |
Autosomal dominant |
| Ectodermal dysplasia, anhidrotic, immunodeficiency, osteoporosis, and lymphedema | IKBKG | Hypomorphic decreasing IKBKG activation of NF-κB | X linked |
| Fetal hydrops | EPHB4 | Inactivating heterozygous missense in the tyrosine kinase domain of EPHB4 | Autosomal dominant |
| Hennekam syndrome type 1 | CCBE1 | Homozygous or compound heterozygous in the calcium-binding EGF domain inhibiting activation of the VEGFC ligand | Autosomal recessive |
| Hennekam syndrome type 2 | FAT4 | Loss of function homozygous or compound heterozygous | Autosomal recessive |
| Hennekam syndrome type 3 | ADAMTS3 | Loss of function bi-allelic missense in the prodomain and the peptidase domain of ADAMTS inhibit activation of the VEGFC ligand | Autosomal recessive |
| Hereditary lymphedema type 3/generalized lymphatic dysplasia of Fotiou | PIEZO1 | Activating or inactivating homozygous or compound heterozygous missense, nonsense, and splice site in the mechanosensitive ion channel PIEZO1 | Autosomal recessive |
| Hypotrichosis-lymphedema-telangiectasia | SOX18 | Loss of function homozygous missense or heterozygous nonsense affecting the alpha-helix of the DNA-binding domain of the transcription factor SOX18 | Autosomal recessive |
| Klippel–Trenaunay syndrome | PIK3CA | Activating missense results in constitutively active PI3K-AKT signaling | Somatic |
| Lymphedema-distichiasis syndrome | FOXC2 | Loss of function heterozygous in the transcription factor FOXC2 | Autosomal dominant |
| Lymphedema-lymphangiectasia | HGF | Possible loss of function results in decreased activation of the c-MET receptor tyrosine kinase | Autosomal dominant |
| Meige disease | GJC2 | Heterozygous missense affecting gap junction protein connexin 47 | Autosomal dominant |
| Microcephaly-chorioretinopathy-lymphedema | KIF11 | Loss of function variable types result in dysfunctional EG5, a kinesin-type motor protein, and activation of PI3K-AKT signaling | Autosomal dominant |
| Milroy-like disease | VEGFC | Loss of function frameshift results in truncated inactive VEGFR-3 ligand | Autosomal dominant |
| Noonan syndrome |
BRAF
MAP2K1 MAP2K2 PTPN11 RIT1 SOS1 |
Variable types result in RAS-MAPK pathway dysregulation | Autosomal dominant |
| Oculodentodigital dysplasia/lymphedema syndrome | GJA1 | Missense affects gap junction protein connexin 43 | Autosomal dominant |
| Parkes-Weber syndrome |
EPHB4
RASA1 |
Inactivating heterozygous missense in the tyrosine kinase domain of EPHB4 Loss of function in the RAS GTPase-activating protein upregulating RAS/MAPK signaling |
Autosomal dominant |
| Primary congenital lymphedema (Milroy disease) | VEGFR-3 | Inactivating missense in the tyrosine kinase domain of VEGFR-3 resulting in decreased downstream signal transduction | Autosomal dominant |
| Primary lymphedema with myelodysplasia (Emberger syndrome) | GATA2 | Loss of function heterozygous truncating in the transcription factor GATA2 | Autosomal dominant |
| Tuberous sclerosis |
TSC1
TSC2 |
Loss of function resulting in constitutive activation of mTOR | Autosomal dominant |
| Turner syndrome | Monosomy X | Chromosomal aneuploidy | X linked |