Allelic Frequencies of Genomic Variants in the NOTCH1 and PTPN11 Genes Associated with Congenital Heart Disease

Abstract

INTRODUCTION: Congenital heart diseases (CHD) are structural defects of the heart or major blood vessels that primarily occur during the embryonic period. The approximate frequency in Colombia is 30% in newborns with malformations. Around 8% of CHD cases are considered monogenic. The genes most frequently associated with CHD are NOTCH1 and PTPN11.

OBJECTIVE: To identify the allelic frequency (AF) of variants in the NOTCH1 and PTPN11 genes in a population from southwestern Colombia.

METHODOLOGY: The results of whole exome sequencing from 320 patients without a CHD diagnosis but with suspected complex diseases were used. Variants in the NOTCH1 and PTPN11 genes were filtered, and the AF of each variant was calculated.

RESULTS: The three most common variants for each gene were recorded. For NOTCH1: c.1669+9T>C (0.353), c.2970-31A>G (0.334), c.5473-43T>C (0.3281); PTPN11: c.854-30T>C (0.0875), c.756+1274G>A (0.078), c.854-21C>T (0.028).

DISCUSSION: For the NOTCH1 gene, Dargis (2015) reported the c.1669+9T>C variant in patients clinically diagnosed with bicuspid aortic valve (BAV). Variants c.2970-31A>G and c.5473-43T>C were identified by Debiec et al. as polymorphic in patients with BAV/Ascending aortic aneurysm. For the PTPN11 gene, Rodriguez et al. reported the variants c.854-30T>C and c.854-21 C>T in patients clinically diagnosed with Noonan syndrome. The variant c.756+1274G>A has not been previously registered in the literature.

CONCLUSIONS: Understanding genomic variants allows the determination of AF in a population, which can increase the risk of disease. Therefore, determining the population AF of these variants enables phenotype-genotype correlations, as well as early diagnosis for precision medicine-based targeted treatment.