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

Abstract

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 ( P = 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.

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

“…The RAS–MAPK signaling pathway is involved in embryonic development during weeks 2 to 8, the critical cardiac development period. Hence, any disturbance to this pathway is likely to cause heart defects [ 21 ]. The SHP-2 protein has an auto-inhibited state in the closed structure by N-SH2–PTP inter-domain interaction.…”

Hereditable variants of classical protein tyrosine phosphatase genes: Will they prove innocent or guilty?

“…The search for a genetic component in congenital heart disease cases revealed that also more subtle PTPN11 variants may have pathological effects, i.e. on the spatio-temporal control of RAS-mediated signals during embryonic heart development ( Xu et al, 2022 ).…”

Discovery of GJC1 (Cx45) as a New Gene Underlying Congenital Heart Disease and Arrhythmias

“…Genetic defects responsible for CHD include aneuploidy (presence of an additional chromosome, absence of a chromosome, or deletion/duplication of one arm of a chromosome), copy number variation (deletion or duplication of a segment of a chromosome), and genetic mutations [ 44 , 45 , 46 ]. To date, pathogenic mutations in over 100 genes have been involved in the occurrence of CHD, of which most encode cardiac transcription factors, cell adhesion molecules, signaling pathway proteins, and cardiac structural proteins essential for cardiovascular morphogenesis [ 44 , 45 , 46 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 ]. However, CHD is of pronounced genetic heterogeneity, and the genetic determinants causative for CHD in a significant proportion of cases remain to be identified.…”