Single ABCA3 mutations increase risk for neonatal respiratory distress syndrome

Jennifer A. Wambach, Daniel J. Wegner, Kelcey DePass, Hillary Heins, Todd E. Druley, Robi D. Mitra, Ping An, Qunyuan Zhang, Lawrence M. Nogee, F. Sessions Cole, Aaron Hamvas

Research output: Contribution to journalArticlepeer-review

58 Scopus citations


BACKGROUND AND OBJECTIVE: Neonatal respiratory distress syndrome (RDS) due to pulmonary surfactant deficiency is heritable, but common variants do not fully explain disease heritability. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Original languageEnglish (US)
Pages (from-to)e1575-e1582
Issue number6
StatePublished - Dec 2012


  • Genetic association studies
  • Neonatal respiratory distress syndrome
  • Newborn
  • Respiratory distress syndrome

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health


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