FLT4 causes developmental disorders of the cardiovascular and lymphovascular systems via pleiotropic molecular mechanisms

Genetic variation in FLT4 is associated with the most prevalent cyanotic congenital heart disease,Tetralogy of Fallot (TOF). Distinct genetic variation in FLT4 is an established cause of Milroy disease, the prevailing form of primary hereditary lymphoedema. Phenotypic features of the conditions are non-overlapping, implying pleiotropic mechanisms. Here, TOF-associated FLT4 variants identified in patients,aggregate in the perinuclear/secretory pathway, activating proteostatic/metabolic signalling that lymphoedema-associated FLT4 variants do not. FLT4 TOF variants display characteristic gene expression changes in developmental signalling pathways, when expressed in undifferentiated human endothelial cells, revealing a role for FLT4 in cardiogenesis distinct from its role in lymphatic development. Inhibition of the main pathways of proteostasis abrogates these effects, identifying potential avenues for therapeutic intervention. We show that a gain-of-pathogenic-function mechanism causes TOF, contrasting with the dominant negative mechanism identified for Milroy-causative variants.This is among the first demonstrations that mechanistically elucidates developmental pleiotropy of thevascular system.