De novo heterozygous variants in the brain-specific transcription factor Neuronal Differentiation Factor 2 (NEUROD2) have been recently associated with early-onset epileptic encephalopathy and developmental delay. Here, we report an adolescent with developmental delay without seizures who was found to have a novel de novo heterozygous NEUROD2 missense variant, p.(Leu163Pro). Functional testing using an in vivo assay of neuronal differentiation in Xenopus laevis tadpoles demonstrated that the patient variant of NEUROD2 displays minimal protein activity, strongly suggesting a loss of function effect. In contrast, a second rare NEUROD2 variant, p.(Ala235Thr), identified in an adolescent with developmental delay but lacking parental studies for inheritance, showed normal in vivo NEUROD2 activity. We thus provide clinical, genetic, and functional evidence that NEUROD2 variants can lead to developmental delay without accompanying early-onset seizures, and demonstrate how functional testing can complement genetic data when determining variant pathogenicity.

Objective

To estimate risk of necrotizing enterocolitis (NEC) for extremely low birth weight (ELBW) infants as a function of preterm formula (PF) and maternal milk intake and calculate the impact of suboptimal feeding on the incidence and costs of NEC.

Study design

We used aORs derived from the Glutamine Trial to perform Monte Carlo simulation of a cohort of ELBW infants under current suboptimal feeding practices, compared with a theoretical cohort in which 90% of infants received at least 98% human milk.

Results

NEC incidence among infants receiving ≥98% human milk was 1.3%; 11.1% among infants fed only PF; and 8.2% among infants fed a mixed diet (P = .002). In adjusted models, compared with infants fed predominantly human milk, we found an increased risk of NEC associated with exclusive PF (aOR = 12.1, 95% CI 1.5, 94.2), or a mixed diet (aOR 8.7, 95% CI 1.2-65.2). In Monte Carlo simulation, current feeding of ELBW infants was associated with 928 excess NEC cases and 121 excess deaths annually, compared with a model in which 90% of infants received ≥98% human milk. These models estimated an annual cost of suboptimal feeding of ELBW infants of $27.1 million (CI $24 million, $30.4 million) in direct medical costs, $563 655 (CI $476 191, $599 069) in indirect nonmedical costs, and $1.5 billion (CI $1.3 billion, $1.6 billion) in cost attributable to premature death.

Conclusions

Among ELBW infants, not being fed predominantly human milk is associated with an increased risk of NEC. Efforts to support milk production by mothers of ELBW infants may prevent infant deaths and reduce costs.