A novel missense mutation and two microrearrangements in the FOXC2 gene of three families with lymphedema-distichiasis syndrome.

Lymphedema-distichiasis (LD) syndrome is a rare autosomal dominant disorder of the FOXC2 gene, which codes for a forkhead transcription factor. Most of the mutations described in this gene to date are deletions or insertions, suggesting a mechanism of haploinsufficiency. We studied three independent families with LD presenting with both lymphedema and distichiasis. Two microrearrangements (one 8-bp deletion and one 7-bp duplication) occurring in a GC-rich genomic region (c.893-930) known to be prone to mutations were identified. A new missense mutation (p.Lys132Glu) located in a highly conserved sequence, the forkhead domain, was also identified. Mutations in this domain have been previously shown to impair FOXC2 transactivation ability. At a genetic level, this study confirms the heterogeneity of mutations responsible for LD and is consistent with a mechanism of haploinsufficiency. At a clinical level, it reinforces the importance of genetic testing in subjects with familial lymphedema or distichiasis, since measures can be taken at an early stage to prevent complications and to reduce the progression of lymphedema or delay its occurrence.