Analysis of lymphoedema-distichiasis families for FOXC2 mutations reveals small insertions and deletions throughout the gene

Lymphoedema-distichiasis (LD) is a dominantly inherited form of primary lym phoedema with onset of lower limb swelling at puberty or later. There is va riable penetrance of this disorder, but the most consistently inherited fea ture is distichiasis, viz. fine hairs arising inappropriately from the meib omian glands. We established linkage of this disorder to 16q24.3 and the ge ne has recently been identified as the forkhead transcription factor FOXC2. We report the mutational analysis of 14 families with LD. All but one of t hese pedigrees have small insertions or deletions in the gene, which seem l ikely to produce haploinsufficiency. The mutation sites are scattered throu ghout the gene. There is one family with a mis-sense mutation in the forkhe ad domain of the protein. This base alteration is not a common polymorphism , is co-inherited with the disease and produces a non-conservative amino ac id change.