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http://purl.uniprot.org/citations/30232381http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/30232381http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/30232381http://www.w3.org/2000/01/rdf-schema#comment"

Purpose

To determine disease-associated single-gene variants in conotruncal defects, particularly tetralogy of Fallot (TOF).

Methods

We analyzed for rare loss-of-function and deleterious variants in FLT4 (VEGFR3) and other genes in the vascular endothelial growth factor (VEGF) pathway, as part of a genome sequencing study involving 175 adults with TOF from a single site.

Results

We identified nine (5.1%) probands with novel FLT4 variants: seven loss-of-function, including an 8-kb deletion, and two predicted damaging. In ten other probands we found likely disruptive variants in VEGF-related genes: KDR (VEGFR2; two stopgain and two nonsynonymous variants), VEGFA, FGD5, BCAR1, IQGAP1, FOXO1, and PRDM1. Detection of VEGF-related variants (19/175, 10.9%) was associated with an increased prevalence of absent pulmonary valve (26.3% vs. 3.4%, p < 0.0001) and right aortic arch (52.6% vs. 29.1%, p = 0.029). Extracardiac anomalies were rare. In an attempt to replicate findings, we identified three loss-of-function or damaging variants in FLT4, KDR, and IQGAP1 in ten independent families with TOF.

Conclusion

Loss-of-function variants in FLT4 and KDR contribute substantially to the genetic basis of TOF. The findings support dysregulated VEGF signaling as a novel mechanism contributing to the pathogenesis of TOF."xsd:string
http://purl.uniprot.org/citations/30232381http://purl.org/dc/terms/identifier"doi:10.1038/s41436-018-0260-9"xsd:string
http://purl.uniprot.org/citations/30232381http://purl.org/dc/terms/identifier"doi:10.1038/s41436-018-0260-9"xsd:string
http://purl.uniprot.org/citations/30232381http://purl.uniprot.org/core/author"Sticht H."xsd:string
http://purl.uniprot.org/citations/30232381http://purl.uniprot.org/core/author"Sticht H."xsd:string
http://purl.uniprot.org/citations/30232381http://purl.uniprot.org/core/author"Walker S."xsd:string
http://purl.uniprot.org/citations/30232381http://purl.uniprot.org/core/author"Walker S."xsd:string
http://purl.uniprot.org/citations/30232381http://purl.uniprot.org/core/author"Scherer S.W."xsd:string
http://purl.uniprot.org/citations/30232381http://purl.uniprot.org/core/author"Scherer S.W."xsd:string
http://purl.uniprot.org/citations/30232381http://purl.uniprot.org/core/author"Curtis M."xsd:string
http://purl.uniprot.org/citations/30232381http://purl.uniprot.org/core/author"Curtis M."xsd:string
http://purl.uniprot.org/citations/30232381http://purl.uniprot.org/core/author"Kim R.H."xsd:string
http://purl.uniprot.org/citations/30232381http://purl.uniprot.org/core/author"Kim R.H."xsd:string
http://purl.uniprot.org/citations/30232381http://purl.uniprot.org/core/author"Costain G."xsd:string
http://purl.uniprot.org/citations/30232381http://purl.uniprot.org/core/author"Costain G."xsd:string
http://purl.uniprot.org/citations/30232381http://purl.uniprot.org/core/author"Hosseini S.M."xsd:string
http://purl.uniprot.org/citations/30232381http://purl.uniprot.org/core/author"Hosseini S.M."xsd:string
http://purl.uniprot.org/citations/30232381http://purl.uniprot.org/core/author"Marshall C.R."xsd:string
http://purl.uniprot.org/citations/30232381http://purl.uniprot.org/core/author"Marshall C.R."xsd:string
http://purl.uniprot.org/citations/30232381http://purl.uniprot.org/core/author"Reuter M.S."xsd:string
http://purl.uniprot.org/citations/30232381http://purl.uniprot.org/core/author"Reuter M.S."xsd:string
http://purl.uniprot.org/citations/30232381http://purl.uniprot.org/core/author"Jobling R."xsd:string
http://purl.uniprot.org/citations/30232381http://purl.uniprot.org/core/author"Jobling R."xsd:string
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