Hereditary lymphedema: evidence for linkage and genetic heterogeneity

Hereditary or primary lymphedema is a developmental disorder of the lymphat ic system which leads to a disabling and disfiguring swelling of the extrem ities. Hereditary lymphedema generally shows an autosomal dominant pattern of inheritance with reduced penetrance, variable expression and variable ag e at onset. Three multigeneration families demonstrating the phenotype of h ereditary lymphedema segregating as an autosomal dominant trait with incomp lete penetrance were genotyped for 366 autosomal markers. RESULTS Linkage a nalysis yielded a two-point LOD score of 6.1 at theta = 0.0 for marker D5S1 354 and a maximum multipoint LOD score of 8.8 at marker D5S1354 located at chromosome 5q34-q35. Linkage analysis in two additional families using mark ers from the linked region showed one family consistent for linkage to dist al chromosome 5, In the second family, linkage to 5q was excluded for all m arkers in the region with LOD scores Z < -2.0. The vascular endothelial gro wth factor C receptor (FLT4) was mapped to the linked region, and partial s equence analysis identified a G-->A transition at nucleotide position 3360 of the FLT4 cDNA, predicting a leucine for proline substitution at residue 1126 of the mature receptor in one nuclear family. This study localizes a g ene for primary lymphedema to distal chromosome 5q, identifies a plausible candidate gene in the linked region, and provides evidence for a second, un linked locus for primary lymphedema.