PTPN11 Gene Mutations and Its Association with the Risk of Congenital Heart Disease.

Congenital heart disease (CHD) is the most common congenital birth defect, with a prevalence of 8.98‰ of all live births in China. PTPN11 has been known to be closely involved in heart developments. In this research, we carried out whole-exome sequencing in nine CHD families and identified eight rare deleterious missense variants of PTPN11 gene in nine probands by stringently filtering criteria. Sanger sequencing of these probands and their unaffected familiar members revealed that six damaging variants were de novo in seven CHD families. Then, targeted sequencing was used to assess the PTPN11 exon variants in 672 sporadic CHD cases and 399 unrelated controls and identified 7 deleterious missense variants in 8 patients. Fisher's exact test reveals a significant association of PTPN11 variations with CHD ( = 0.0289). We observed the distribution of different subtypes in CHD patients with PTPN11 variants and found atrial septal defect (ASD) is a prominent phenotype (58.8%, 10/17). In vitro functional assays revealed that the predicted PTPN11 variants disturb RAS-mitogen-activated protein kinase signaling activity by influencing the phosphorylation level of pathway proteins and increasing the proliferation and migration abilities of cardiomyocytes to different extents. Our findings demonstrated that PTPN11 variants were associated with increased risk of CHD development and may be served as an important susceptible genetic event for CHD, especially the ASD subphenotype.