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Prenat Diagn. 2015 Jun;35(6):517-28. doi: 10.1002/pd.4586. Epub 2015 May 19.

Why increased nuchal translucency is associated with congenital heart disease: a systematic review on genetic mechanisms.

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Department of Obstetrics and Gynaecology, VU University Medical Center, Amsterdam, The Netherlands.
Department of Obstetrics and Gynaecology, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Anatomy, Embryology & Physiology, Academic Medical Center, Amsterdam, The Netherlands.
Department of Obstetrics, Leiden University Medical Center, Leiden, The Netherlands.


This overview provides insight into the underlying genetic mechanism of the high incidence of cardiac defects in fetuses with increased nuchal translucency (NT). Nuchal edema, the morphological equivalent of increased NT, is likely to result from abnormal lymphatic development and is strongly related to cardiac defects. The underlying genetic pathways are, however, unknown. This study aims to present a systematic overview of genes involved in both cardiac and lymphatic development in mouse embryos. A search of PubMed and the Mammalian Phenotype Browser was performed. Fifteen candidate genes involved in both cardiac and lymphatic development were identified: Adrenomedullin; Chicken ovalbumin upstream promoter-transcription factor 2 (COUP-TFII); Cyp51; Ephrin-B2; Forkhead box protein C2 (Foxc2); Nuclear factor of activated T cells, cytoplasmic 1 (Nfatc1); Neurofibromatosis type 1 (Nf1); Phosphoinositide 3-kinase encoding isoform p110α (Pik3ca); Podoplanin; Prospero-related homeobox 1 (Prox1); T-box 1 (Tbx1); Tyrosine kinase with immunoglobulin-like and endothelial growth factor-like domains 1 (Tie1); vascular endothelial growth factor (Vegf)-A; Vegf receptor-3 (Vegfr-3); and Vascular endothelial zinc finger 1 (Vezf1). Mutations in all but one gene (Pik3ca) resulted in both a cardiac defect and nuchal edema. Candidate genes - mainly encoding for endothelium - are involved in both cardiac and lymphatic development. Alterations in candidate genes are associated with the strong relation between increased NT and cardiac defects.

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