A NOVEL MISSENSE MUTATION AND TWO MICROREARRANGEMENTS IN THE FOXC2 GENE OF THREE FAMILIES WITH LYMPHEDEMA-DISTICHIASIS SYNDROME

Abstract

Lymphedema-distichiasis (LD) syndromeis a rare autosomal dominant disorder of theFOXC2 gene, which codes for a forkheadtranscription factor. Most of the mutationsdescribed in this gene to date are deletions orinsertions, suggesting a mechanism of haploinsufficiency.We studied three independentfamilies with LD presenting with bothlymphedema and distichiasis. Two microrearrangements(one 8-bp deletion and one7-bp duplication) occurring in a GC-richgenomic region (c.893-930) known to be proneto mutations were identified. A new missensemutation (p.Lys132Glu) located in a highlyconserved sequence, the forkhead domain, wasalso identified. Mutations in this domain havebeen previously shown to impair FOXC2transactivation ability. At a genetic level, thisstudy confirms the heterogeneity of mutationsresponsible for LD and is consistent with amechanism of haploinsufficiency. At a clinicallevel, it reinforces the importance of genetictesting in subjects with familial lymphedemaor distichiasis, since measures can be taken atan early stage to prevent complications and toreduce the progression of lymphedema ordelay its occurrence.