gene variants in term newborns with congenital heart defects and necrotizing enterocolitis.

Background: Necrotizing enterocolitis (NEC) is a common gastrointestinal emergency among neonates which is characterized by acute intestinal inflammation and necrosis. The main risk factors for NEC are prematurity, low birth weight, and some preexisting health conditions such as congenital heart defects (CHDs). Investigation of the potential genetic predisposition to NEC is a promising approach that might provide new insights into its pathogenesis. One of the most important proteins that play a significant role in the pathogenesis of NEC is Toll-like receptor 4 (TLR4) which recognizes lipopolysaccharide found in Gram-negative bacteria. In intestinal epithelial cells, a protein encoded by the gene is a major inhibitor of TLR4 signaling. A few variants, including rare p.Y168X and p.S80Y, have already been identified in preterm infants with NEC, but their pathogenic significance remains unclear. This study aimed to investigate the spectrum of genetic variants in term newborns with CHD and to assess their potential association with NEC.

Methods And Results: A total of 93 term newborns with critical CHD were enrolled in this study, 33 of them developed NEC. genetic variants were determined by Sanger sequencing of all exons. In total, eight genetic variants were identified, two of which were found only in newborns with NEC ( = 0.12). The rare missense p.S80Y (rs117739035) variant in exon 4 was found in two infants with NEC stage IIA. Two infants with NEC stage III and stage IB carried a novel duplication c. 102_121dup (rs552367848) variant in exon 10 that has not been previously associated with any clinical phenotype.

Conclusions: The presence of both variants only in neonates who developed NEC, together with earlier published data, may suggest their potential contribution to the risk of developing NEC in term infants with CHD and allow planning larger cohort studies to clarify their relevance.