Autosomal dominant mannose-binding lectin deficiency is associated with worse neurodevelopmental outcomes after cardiac surgery in infants

Abstract

Objectives: The MBL2 gene is the major genetic determinant of mannose-binding lectin (MBL)-an acute phase reactant. Low MBL levels have been associated with adverse outcomes in preterm infants. The MBL2_Gly54Asp missense variant causes autosomal dominant MBL deficiency. We tested the hypothesis that MBL2_Gly54Asp is associated with worse neurodevelopmental outcomes after cardiac surgery in neonates.

Methods: This is an analysis of a previously described cohort of patients with nonsyndromic congenital heart disease who underwent cardiac surgery with cardiopulmonary bypass before age 6 months (n = 295). Four-year neurodevelopment was assessed in 3 domains: Full-Scale Intellectual Quotient, the Visual Motor Integration development test, and the Child Behavior Checklist to assess behavior problems. The Child Behavior Checklist measured total behavior problems, pervasive developmental problems, and internalizing/externalizing problems. A multivariable linear regression model, adjusting for confounders, was fit.

Results: MBL2_Gly54Asp was associated with a significantly increased covariate-adjusted pervasive developmental problem score (β = 3.98; P = .0025). Sensitivity analyses of the interaction between age at first surgery and MBL genotype suggested effect modification for the patients with MBL2_Gly54Asp (P_interaction = .039), with the poorest neurodevelopment outcomes occurring in children who had surgery earlier in life.

Conclusions: We report the novel finding that carriers of MBL2_Gly54Asp causing autosomal dominant MBL deficiency have increased childhood pervasive developmental problems after cardiac surgery, independent of other covariates. Sensitivity analyses suggest that this effect may be larger in children who underwent surgery at earlier ages. These data support the role of nonsyndromic genetic variation in determining postsurgical neurodevelopment-related outcomes in children with congenital heart disease.

Keywords: MBL2; congenital heart disease; gene-by-environment interaction; gene-environment interactions; genetics; mannose-binding lectin; neurodevelopment.

Figure 1. Effect of MBL deficient genotype is modified by age at first surgery, with infants receiving surgery at an early age having significantly higher pervasive developmental problems scores (P_interaction=0.039)

Predicted values of CBCL/1.5-5 PDP score are 59.7 – 0.0372 × (Age at first surgery, in days) for the MBL deficient genotype group and 55.72 – 0.0012 × (Age at first surgery, in days) for the normal MBL group.