Congenital heart Disease (CHD) affects almost 1% of live births1. CHD is genetically heterogeneous, with hundreds of disease genes2. Identification of genetic variants involved in CHD, and genotype-phenotype comparison might provide novel mechanistic insight in the pathomechanisms of CHD and the developmental mechanisms which orchestrate human heart development. However, such studies are challenging, and often require comparison of clinical, genetic and functional data.
Rare variants in FLT4, encoding vascular endothelial growth factor receptor3 (VEGFR3), have been associated with CHD (in particular Tetralogy of Fallot)2,3 and rare hereditary malformations of the lymphatic system (LMPHM1, OMIM # 153100)4. Interestingly, phenotypic overlap between the two conditions are usually not observed in patients, and the FLT4 variants causing each phenotype are distinct, thus suggesting developmental pleiotrophy. In a recently published article, Monaghan et al. compared the effect of FLT4 variants associated with CHD and LMPHM1, respectively, by functional analysis in cell models and zebrafish. The study confirmed distinct cellular consequences of FLT4 variants, associated with CHD, and provided novel insight into the pathomechanism. Based on their results, the authors conclude that CHD associated FLT4 variants disrupts posttranslational processing of the VEGFR3 receptor. Interestingly, in vitro experiments with proteostasis inhibitors suggested partial rescue of the effects of CHD associated FLT4 variants, suggesting a possible translational potential.
In summary, this article represents an interesting multidisciplinary approach to study the pathomechanism of CHD-causing variants.
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