title: Comprehensive genetic variant discovery in the surfactant protein B gene.
abstract: Completely penetrant mutations in the surfactant protein B gene (SFTPB) and >75% reduction of SFTPB expression disrupt pulmonary surfactant function and cause neonatal respiratory distress syndrome. To inform studies of genetic regulation of SFTPB expression, we created a catalogue of SFTPB variants by comprehensive resequencing from an unselected, population-based cohort (n = 1,116). We found an excess of low-frequency variation [81 SNPs and five small insertion/deletions (in/dels)]. Despite its small genomic size (9.7 kb), SFTPB was characterized by weak linkage disequilibrium (LD) and high haplotype diversity. Using the HapMap Yoruban and European populations, we identified a recombination hot spot that spans SFTPB, was not detectable in our focused resequencing data, and accounts for weak LD. Using homology-based software tools, we discovered no definitively damaging exonic variants. We conclude that excess low-frequency variation, intragenic recombination and lack of common disruptive exonic variants favor complete resequencing as the optimal approach for genetic association studies to identify regulatory SFTPB variants that cause neonatal respiratory distress syndrome in genetically diverse populations.
authors.affiliation: Edward Mallinckrodt Department of Pediatrics,Washington University School of Medicine and St. Louis Children's Hospital, St. Louis, Missouri 63110, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Hamvas
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wegner
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Carlson
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Bergmann
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Trusgnich
authors.forename: Lucinda
authors.initials: L
authors.lastname: Fulton
authors.forename: Yumi
authors.initials: Y
authors.lastname: Kasai
authors.forename: Ping
authors.initials: P
authors.lastname: An
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
authors.forename: F Sessions
authors.initials: FS
authors.lastname: Cole
mesh_terms: D001741:Black or African American / Q000235:genetics; D044466:Asian People / Q000235:genetics; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D030561:Databases, Nucleic Acid; D019143:Evolution, Molecular; D005091:Exons; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006239:Haplotypes; D006801:Humans; D007231:Infant, Newborn; D007438:Introns; D015810:Linkage Disequilibrium; D016254:Mutagenesis, Insertional; D015997:Neonatal Screening / Q000379:methods*; D020641:Polymorphism, Single Nucleotide; D011159:Population Surveillance; D037701:Pulmonary Surfactant-Associated Protein B / Q000235:genetics*; D011995:Recombination, Genetic; D012127:Respiratory Distress Syndrome, Newborn / Q000208:ethnology / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D037701:Pulmonary Surfactant-Associated Protein B