Characterization of genomic variants of the PTPN11 gene associated with congenital heart disease in a population of southwestern Colombia.

Background: Congenital heart disease (CHD) are problems in the structure and functioning of the heart, or the great vessels, affecting 1% of live newborns.

Case study: 8% of CHD are monogenic. Variants in the PTPN11 gene have been associated with septal defects and aortic pulmonary stenosis.

Methods: The results of whole exome sequencing of 320 patients without a diagnosis of CHD with suspected complex disease were used, filtering the variants of the PTPN11 gene, databases such as Clinvar and Varsome, and predictive software of clinical significance such as UMD-Predictor were used. , Mutation assessor, Polyphen-2, SIFT, CADD, Human Splicing Finder according to the ACMG; Calculation of the allele frequencies (AF) of each variant and gene interaction networks was performed in the Genemania program.

Results: PTPN11 presented 36 variants, 10 reported (1 synonymous and 9 intronic), the bioinformatic analysis reported 7 benign variants, 2 VOUS, and one pathogenic variant, c. 854-30T>C, also being the variant with the highest FA (0.0875). This gene showed interactions with FRS2, SPRY1, PDGFRB and INSR.

Discussion: The PTPN11 gene encodes protein tyrosine phosphatase (PTP or SH2), found mostly in the heart. The c.854-30T>C variant has not been recorded in patients with congenital heart disease. FRS2, PTPN11, and GRB2 form a complex in response to FGFR stimulation, FRS2 important in mediating the RAS/MAPK signaling cascade important for cell migration, differentiation, and proliferation. PTPN11 inactivates the inhibitor SPRY1 and upregulates the FGF signaling pathway for cell growth, differentiation and migration, PTPN11 promotes protein kinase receptor activation of the PDGRFB receptor signal pathway in cardiac smooth muscle cells; INSR is important for mobilizing the MAPK signaling pathway.

Conclusion Knowing the variants and their frequency allows for phenotype-genotype correlations, early diagnosis for targeted treatment based on precision medicine.