Applying deep DNA sequencing to common, complex pediatric traits.

The specific genetic factors contributing to the causes of complex pediatric diseases are gradually being identified through a combination of technological advances, advanced statistical methods, and large biorepositories with appropriate samples and data. These developments have the capacity to personalize diagnosis and treatment of the common complications faced by preterm infants. The article in this issue of Pediatrics by Wambach et al is illustrative of this transformation and was applied to respiratory distress syndrome (RDS), the most common respiratory morbidity associated with prematurity. The authors considered RDS as a complex disease with both genetic and environmental/developmental risk factors. By excluding infants of ,34 weeks’ gestation, a sample cohort was studied that was enriched for genetic causes of RDS and depleted of some developmental risk factors. They examined several genes previously associated with Mendelian single-gene (recessive usually) contributors to RDS that may be severe even in the term neonate. They searched for heterozygotes of known mutations or more minor variants that would result in a less-extreme phenotype but still be significant contributors to RDS in the near-term infant. Their finding that ABCA3 mutations are overrepresented in preterm infants with RDS compared with those without RDS is consistent with a growing body of literature demonstrating that a non-Mendelian complex disease may be caused by alterations in the same gene responsible for a more severe syndromic, single-gene effect, presentation. Although complex traits are usually thought of as arising from the interplay of many genetic and environmental factors, each of small-effect, current work suggests that recently arising rare variants may individually have a substantial impact on a disease phenotype. These effects are driven by what is a presumably lower dose of a “genetic abnormality.” Although they focused on coding sequence variants to assist in determining causality by using functional modeling, the study strongly suggests that future studies should also focus on regulatory regions for ABCA3 where the protein structure may be intact but dosage altered. If these results are confirmed, it will allow for more accurate diagnosis and estimation of recurrences in subsequent pregnancies with perhaps altering plans for delivery hospital or intensity of monitoring of term or near-term infants for RDS after birth.