Single <i>ABCA3</i> Mutations Increase Risk for Neonatal Respiratory Distress Syndrome

TLDR

Neonatal respiratory distress syndrome is a heritable surfactant deficiency, yet common variants do not fully explain its heritability, and ABCA3 mutations—though individually rare—are collectively common in European and African descent populations. The study used pooled next‑generation sequencing of all exons of five surfactant‑associated genes in race‑stratified infants ≥34 weeks’ gestation, followed by in‑silico functional prediction, independent genotyping validation, and race‑specific frequency comparison to assess disease association. Single ABCA3 mutations were significantly overrepresented in European‑descent RDS infants (14.3 % vs 3.7 %) and accounted for ~10.9 % of attributable risk, but were not overrepresented in African‑descent infants, and no other surfactant genes contributed to population‑based disease burden.

Abstract

Neonatal respiratory distress syndrome (RDS) due to pulmonary surfactant deficiency is heritable, but common variants do not fully explain disease heritability.Using next-generation, pooled sequencing of race-stratified DNA samples from infants ≥34 weeks' gestation with and without RDS (n = 513) and from a Missouri population-based cohort (n = 1066), we scanned all exons of 5 surfactant-associated genes and used in silico algorithms to identify functional mutations. We validated each mutation with an independent genotyping platform and compared race-stratified, collapsed frequencies of rare mutations by gene to investigate disease associations and estimate attributable risk.Single ABCA3 mutations were overrepresented among European-descent RDS infants (14.3% of RDS vs 3.7% of non-RDS; P = .002) but were not statistically overrepresented among African-descent RDS infants (4.5% of RDS vs 1.5% of non-RDS; P = .23). In the Missouri population-based cohort, 3.6% of European-descent and 1.5% of African-descent infants carried a single ABCA3 mutation. We found no mutations among the RDS infants and no evidence of contribution to population-based disease burden for SFTPC, CHPT1, LPCAT1, or PCYT1B.In contrast to lethal neonatal RDS resulting from homozygous or compound heterozygous ABCA3 mutations, single ABCA3 mutations are overrepresented among European-descent infants ≥34 weeks' gestation with RDS and account for ~10.9% of the attributable risk among term and late preterm infants. Although ABCA3 mutations are individually rare, they are collectively common among European- and African-descent individuals in the general population.