title: Single ABCA3 mutations increase risk for neonatal respiratory distress syndrome.
abstract: 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.
authors.affiliation: Division of Newborn Medicine, The Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St Louis, MO 63110. wambach_j@kids.wustl.edu
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wambach
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wegner
authors.forename: Kelcey
authors.initials: K
authors.lastname: Depass
authors.forename: Hillary
authors.initials: H
authors.lastname: Heins
authors.forename: Todd E
authors.initials: TE
authors.lastname: Druley
authors.forename: Robi D
authors.initials: RD
authors.lastname: Mitra
authors.forename: Ping
authors.initials: P
authors.lastname: An
authors.forename: Qunyuan
authors.initials: Q
authors.lastname: Zhang
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Nogee
authors.forename: F Sessions
authors.initials: FS
authors.lastname: Cole
authors.forename: Aaron
authors.initials: A
authors.lastname: Hamvas
mesh_terms: D008243:1-Acylglycerophosphocholine O-Acyltransferase / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D001741:Black or African American / Q000235:genetics; D019916:Choline-Phosphate Cytidylyltransferase / Q000235:genetics; D015331:Cohort Studies; D002798:Diacylglycerol Cholinephosphotransferase / Q000235:genetics; D059472:Exome / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics*; D005865:Gestational Age; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D009154:Mutation; D037721:Pulmonary Surfactant-Associated Protein C / Q000235:genetics; D012127:Respiratory Distress Syndrome, Newborn / Q000208:ethnology / Q000235:genetics*; D012306:Risk; D044465:White People / Q000235:genetics
chemical_list: C441524:ABCA3 protein, human; D018528:ATP-Binding Cassette Transporters; D037721:Pulmonary Surfactant-Associated Protein C; C489679:SFTPC protein, human; D008243:1-Acylglycerophosphocholine O-Acyltransferase; C526202:Lpcat1 protein, human; D019916:Choline-Phosphate Cytidylyltransferase; C545697:PCYT1B protein, human; D002798:Diacylglycerol Cholinephosphotransferase