title: Population and disease-based prevalence of the common mutations associated with surfactant deficiency.
abstract: The prevalence of the common mutations in the surfactant protein-B (121ins2), surfactant protein-C (I73T), and ATP-binding cassette member A3 (E292V) genes in population-based or case-control cohorts of newborn respiratory distress syndrome (RDS) is unknown. We determined the frequencies of these mutations in ethnically diverse population and disease-based cohorts using restriction enzyme analysis (121ins2 and E292V) and a 5' nuclease assay (I73T) in DNA samples from population-based cohorts in Missouri, Norway, South Korea, and South Africa, and from a case-control cohort of newborns with and without RDS (n = 420). We resequenced the ATP-binding cassette member A3 gene (ABCA3) in E292V carriers and computationally inferred ABCA3 haplotypes. The population-based frequencies of 121ins2, E292V, and I73T were rare (<0.4%). E292V was present in 3.8% of newborns with RDS, a 10-fold greater prevalence than in the Missouri cohort (p < 0.001). We did not identify other loss of function mutations in ABCA3 among patients with E292V that would account for their RDS. E292V occurred on a unique haplotype that was derived from a recombination of two common ABCA3 haplotypes. E292V was over-represented in newborns with RDS suggesting that E292V or its unique haplotype impart increased genetic risk for RDS.
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Tami H
authors.initials: TH
authors.lastname: Garmany
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wambach
authors.forename: Hillary B
authors.initials: HB
authors.lastname: Heins
authors.forename: Julie M
authors.initials: JM
authors.lastname: Watkins-Torry
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wegner
authors.forename: Kate
authors.initials: K
authors.lastname: Bennet
authors.forename: Ping
authors.initials: P
authors.lastname: An
authors.forename: Garland
authors.initials: G
authors.lastname: Land
authors.forename: Ola D
authors.initials: OD
authors.lastname: Saugstad
authors.forename: Howard
authors.initials: H
authors.lastname: Henderson
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: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007723:Korea; D008297:Male; D008923:Missouri; D009154:Mutation; D009664:Norway; D011159:Population Surveillance; D037701:Pulmonary Surfactant-Associated Protein B / Q000172:deficiency / Q000235:genetics*; D037721:Pulmonary Surfactant-Associated Protein C / Q000172:deficiency / Q000235:genetics*; D012127:Respiratory Distress Syndrome, Newborn / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D013019:South Africa
chemical_list: C441524:ABCA3 protein, human; D018528:ATP-Binding Cassette Transporters; D037701:Pulmonary Surfactant-Associated Protein B; D037721:Pulmonary Surfactant-Associated Protein C; C489679:SFTPC protein, human