title: Inherited surfactant deficiency caused by uniparental disomy of rare mutations in the surfactant protein-B and ATP binding cassette, subfamily a, member 3 genes.
abstract: OBJECTIVE
  To characterize inheritance of homozygous, rare, recessive loss-of-function mutations in surfactant protein-B (SFTPB) or ATP binding cassette, subfamily A, member 3 (ABCA3) genes in newborns with lethal respiratory failure.
  
  
  METHODS
  We resequenced genes from parents whose infants were homozygous for mutations in SFTPB or ABCA3. For infants with only 1 heterozygous parent, we performed microsatellite analysis for chromosomes 2 (SFTPB) and 16 (ABCA3).
  
  
  RESULTS
  We identified 1 infant homozygous for the g.1549C > GAA mutation (121ins2) in SFTPB for whom only the mother was heterozygous and 3 infants homozygous for mutations in ABCA3 (p.K914R, p.P147L, and c.806_7insGCT) for whom only the fathers were heterozygous. For the SP-B-deficient infant, microsatellite markers confirmed maternal heterodisomy with segmental isodisomy. Microsatellite analysis confirmed paternal isodisomy for the 3 ABCA3-deficient infants. Two ABCA3-deficient infants underwent lung transplantation at 3 and 5 months of age, respectively, and 2 infants died. None exhibited any nonpulmonary phenotype.
  
  
  CONCLUSIONS
  Uniparental disomy should be suspected in infants with rare homozygous mutations in SFTPB or ABCA3. Confirmation of parental carrier status is important to provide recurrence risk and to monitor expression of other phenotypes that may emerge through reduction to homozygosity of recessive alleles.
authors: Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine and St. Louis Children's Hospital, St. Louis, MO 63110, USA. hamvas@kids.wustl.edu
authors: Aaron
authors: A
authors: Hamvas
authors: Lawrence M
authors: LM
authors: Nogee
authors: Daniel J
authors: DJ
authors: Wegner
authors: Kelcey
authors: K
authors: Depass
authors: John
authors: J
authors: Christodoulou
authors: Bruce
authors: B
authors: Bennetts
authors: Leon R
authors: LR
authors: McQuade
authors: Peter H
authors: PH
authors: Gray
authors: Robin R
authors: RR
authors: Deterding
authors: Travis R
authors: TR
authors: Carroll
authors: Anja
authors: A
authors: Kammesheidt
authors: Laura M
authors: LM
authors: Kasch
authors: Shashikant
authors: S
authors: Kulkarni
authors: F Sessions
authors: FS
authors: Cole
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation / Q000235:genetics*; D037701:Pulmonary Surfactant-Associated Protein B / Q000172:deficiency* / Q000235:genetics*; D024182:Uniparental Disomy / Q000175:diagnosis* / Q000235:genetics*
chemical_list: C441524:ABCA3 protein, human; D018528:ATP-Binding Cassette Transporters; D037701:Pulmonary Surfactant-Associated Protein B