The role of genetics in the pathogenesis of necrotizing enterocolitis (NEC) was initially informed by epidemiological data indicating differences in prevalence among different ethnic groups as well as concordance in twins. These early observations, together with major advances in genomic research, paved the way for studies that begin to reveal the contribution of genetics to NEC. Using the candidate gene- or pathway approach, several potential pathogenic variants for NEC in premature infants have already been identified. More recently, exome- and genome-wide association study for NEC has also been completed. These advances, however, are tempered by the lack of adequately powered replication cohorts to validate the accuracy of these discoveries. Despite many challenges, genetic research in NEC is expected to increase, providing new insights into its pathogenesis and bringing the promise of personalized care closer to reality. In this review we provide a summary of genetic studies in NEC along with defining the challenges and possible future approaches.

Bilateral renal agenesis leads to anhydramnios and other sequelae including pulmonary hypoplasia. There have been rare case reports of normal pulmonary function in the presence of bilateral renal agenesis in monoamniotic discordant twins, but this has never been reported in a singleton pregnancy. The few reported cases in twins have all been fatal in the neonatal period with no reported cases of survival beyond 2 months. We describe the first case of a singleton infant with bilateral renal agenesis who had normal pulmonary function and did well on peritoneal dialysis for 4 years while awaiting a renal transplant.

Aberrant toll-like receptor (TLR) activation is central to necrotizing enterocolitis (NEC) pathogenesis. β2 integrins regulate TLR signaling, and integrin β2 (ITGB2) deficiency causes TLR hyperresponsiveness. To test the hypothesis that ITGB2 genetic variants modulate NEC susceptibility, we sequenced the exonic ITGB2 locus to compare the prevalence of deleterious variants among 221 preterm infants with and without NEC. ITGB2 variants were not associated with NEC in our entire cohort (NEC [9/56] versus controls [16/165], P = 0.19) or in extremely low birthweight infants (ELBW, controls [7.9%] versus NEC [18.2%]; P = 0.11) but were increased compared to the populace (4.5%, gnomad.broadinstitute.org). Combined annotation-dependent depletion -predicted deleterious ITGB2 variants increased proportionately with increasing NEC severity in ELBW infants (controls [6.7%] versus medical NEC [16.7%] versus surgical NEC [19%] (P = 0.03). Although ITGB2 variants were not associated with NEC in our preterm cohort, subgroup analysis showed a trend towards enrichment with NEC severity in ELBW infants.

Our data do not support routine vancomycin prophylaxis prior to PICC line removal in premature infants to prevent sepsis associated with PICC removal. However, a large randomized controlled trial is further needed to delineate these results.