Alternative titles; symbols
ORPHA: 568051; DO: 0070208;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q42.13 | Lymphatic malformation 3 | 613480 | Autosomal dominant | 3 | GJC2 | 608803 |
A number sign (#) is used with this entry because of evidence that lymphatic malformation-3 (LMPHM3) is caused by heterozygous mutation in the GJC2 gene (608803) on chromosome 1q42.
Hereditary primary lymphedema is caused by anatomic or functional defects in the lymphatic system, resulting in chronic swelling of body parts. There may be accompanying nail and skin changes, such as nail dysplasia or papillomatosis. Onset is usually at birth or in early childhood but can occur later, and the severity is variable (summary by Gordon et al., 2013 and Balboa-Beltran et al., 2014).
For a discussion of genetic heterogeneity of lymphatic malformation, see 153100.
Ferrell et al. (2010) reported 2 unrelated families with autosomal dominant inheritance of lymphedema. In 1 family, age at onset ranged from before 1 year to 15 years. Affected individuals had onset of uncomplicated lymphedema of the lower limbs, and some later developed upper limb involvement. Four had recurrent skin infections. In the second family, age at onset was between 10 and 21 years, and 2 patients developed cellulitis.
Ostergaard et al. (2011) reported 5 unrelated families with primary lymphedema. The age of initial presentation ranged from birth to 40 years, but most had onset in the first or second decade. Severity ranged from mild swelling below the knees to severe swelling of all 4 limbs. Severely affected individuals had multiple episodes of cellulitis. Lymph scans, when performed, showed impaired lymphatic drainage consistent with distal hypoplasia of the lymphatics and variable incompetence of the great saphenous vein.
The transmission pattern of primary lymphedema in the families reported by Ferrell et al. (2010) and Ostergaard et al. (2011) was consistent with autosomal dominant inheritance.
By genomewide linkage analysis of a family with autosomal dominant primary lymphedema, Ostergaard et al. (2011) found linkage to a 16.1-Mb region on chromosome 1q42 between SNPs rs10494988 and rs1043909 (maximum lod score of 2.94).
In affected members of 2 large families with autosomal dominant hereditary lymphedema, Ferrell et al. (2010) identified 2 different heterozygous mutations in the GJC2 gene (608803.0009 and 608803.0010). Both mutations affected the extracellular domain. Incomplete penetrance was observed. Ferrell et al. (2010) hypothesized that the mutations might result in impaired channel activity, which could cause impaired coordination of pulsatile lymphatic flow. Four additional putative mutations in the GJC2 gene were identified in 4 smaller families with lymphedema; no functional studies were performed.
By linkage analysis followed by whole-exome sequencing, Ostergaard et al. (2011) identified a heterozygous mutation in the GJC2 gene (S48L; 608803.0011) in 8 affected members of a family with autosomal dominant primary lymphedema. Genetic analysis of another affected family identified the same pathogenic mutation. Further sequencing of this gene in 19 unrelated individuals with lymphedema identified 3 with mutations in the GJC2 gene, 2 of whom also carried the S48L substitution. Ostergaard et al. (2011) concluded that mutations in GJC2 are a significant cause of autosomal dominant primary lymphedema.
Balboa-Beltran, E., Fernandez-Seara, M. J., Perez-Munuzuri, A., Lago, R., Garcia-Magan, C., Couce, M. L., Sobrino, B., Amigo, J., Carracedo, A., Barros, F. A novel stop mutation in the vascular endothelial growth factor-C gene (VEGFC) results in Milroy-like disease. J. Med. Genet. 51: 475-478, 2014. Note: Erratum: J. Med. Genet. 52: 216 only, 2015. [PubMed: 24744435] [Full Text: https://doi.org/10.1136/jmedgenet-2013-102020]
Ferrell, R. E., Baty, C. J., Kimak, M. A., Karlsson, J. M., Lawrence, E. C., Franke-Snyder, M., Meriney, S. D., Feingold, E., Finegold, D. N. GJC2 missense mutations cause human lymphedema. Am. J. Hum. Genet. 86: 943-948, 2010. [PubMed: 20537300] [Full Text: https://doi.org/10.1016/j.ajhg.2010.04.010]
Gordon, K., Schulte, D., Brice, G., Simpson, M. A., Roukens, M. G., van Impel, A., Connell, F., Kalidas, K., Jeffery, S., Mortimer, P. S., Mansour, S., Schulte-Merker, S., Ostergaard, P. Mutation in vascular endothelial growth factor-C, a ligand for vascular endothelial growth factor receptor-3, is associated with autosomal dominant Milroy-like primary lymphedema. Circ. Res. 112: 956-960, 2013. [PubMed: 23410910] [Full Text: https://doi.org/10.1161/CIRCRESAHA.113.300350]
Ostergaard, P., Simpson, M. A., Brice, G., Mansour, S., Connell, F. C., Onoufriadis, A., Child, A. H., Hwang, J., Kalidas, K., Mortimer, P. S., Trembath, R., Jeffery, S. Rapid identification of mutations in GJC2 in primary lymphoedema using whole exome sequencing combined with linkage analysis with delineation of the phenotype. J. Med. Genet. 48: 251-255, 2011. [PubMed: 21266381] [Full Text: https://doi.org/10.1136/jmg.2010.085563]