A novel stop-gain pathogenic variant in FLT4 and a nonsynonymous pathogenic variant in PTPN11 associated with congenital heart defects

Abstract

Background Congenital heart defects (CHDs) are the most common congenital malformations, including structural malformations in the heart and great vessels. CHD complications such as low birth weight, prematurity, pregnancy termination, mortality, and morbidity depend on the type of defect. Methods In the present research, genetic analyses via whole-exome sequencing (WES) was performed on 3 unrelated pedigrees with CHDs. The candidate variants were confirmed, segregated by PCR-based Sanger sequencing, and evaluated by bioinformatics analysis. Results A novel stop-gain c.C244T:p.R82X variant in the FLT4 gene, as well as a nonsynonymous c.C1403T:p.T468M variant in the PTPN11 gene, was reported by WES. FLT4 encodes a receptor tyrosine kinase involved in lymphatic development and is known as vascular endothelial growth factor 3. Conclusions We are the first to report a novel c.C244T variant in the FLT4 gene associated with CHDs. Using WES, we also identified a nonsynonymous variant affecting protein-tyrosine phosphatase, the non-receptor type 11 (PTPN11) gene. The clinical implementation of WES can determine gene variants in diseases with high genetic and phenotypic heterogeneity like CHDs.

Role of Lymphangiogenesis in Cardiac Repair and Regeneration

“…A recent study found that the CHD tetralogy of Fallot is associated with loss-of-function mutations in VEGFR-3, which is encoded by Flt4. 65 In addition, Flt4 variants also cause Milroy disease, one of the main forms of hereditary primary lymphedema. Interestingly, the mutation of Flt4 in CHD is different from the mutation of Flt4 in Milroy's disease.…”