Genotype-phenotype correlations for infants and children with ABCA3 deficiency

Am J Respir Crit Care Med. 2014 Jun 15;189(12):1538-43. doi: 10.1164/rccm.201402-0342OC.


Rationale: Recessive mutations in the ATP-binding cassette transporter A3 (ABCA3) cause lethal neonatal respiratory failure and childhood interstitial lung disease. Most ABCA3 mutations are private.

Objectives: To determine genotype-phenotype correlations for recessive ABCA3 mutations.

Methods: We reviewed all published and unpublished ABCA3 sequence and phenotype data from our prospective genetic studies of symptomatic infants and children at Washington and Johns Hopkins Universities. Mutations were classified based on their predicted disruption of protein function: frameshift and nonsense mutations were classified as "null," whereas missense, predicted splice site mutations, and insertion/deletions were classified as "other." We compared age of presentation and outcomes for the three genotypes: null/null, null/other, and other/other.

Measurements and main results: We identified 185 infants and children with homozygous or compound heterozygous ABCA3 mutations and lung disease. All of the null/null infants presented with respiratory failure at birth compared with 75% of infants with null/other or other/other genotypes (P = 0.00011). By 1 year of age, all of the null/null infants had died or undergone lung transplantation compared with 62% of the null/other and other/other children (P < 0.0001).

Conclusions: Genotype-phenotype correlations exist for homozygous or compound heterozygous mutations in ABCA3. Frameshift or nonsense ABCA3 mutations are predictive of neonatal presentation and poor outcome, whereas missense, splice site, and insertion/deletions are less reliably associated with age of presentation and prognosis. Counseling and clinical decision making should acknowledge these correlations.

Keywords: childhood interstitial lung disease; neonatal respiratory distress; surfactant.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / deficiency*
  • ATP-Binding Cassette Transporters / genetics
  • Child
  • Child, Preschool
  • Female
  • Genetic Association Studies*
  • Genetic Markers
  • Heterozygote
  • Homozygote
  • Humans
  • Infant
  • Infant, Newborn
  • Lung Diseases, Interstitial / genetics*
  • Lung Diseases, Interstitial / mortality
  • Lung Diseases, Interstitial / surgery
  • Lung Transplantation
  • Male
  • Mutation*
  • Respiratory Distress Syndrome, Newborn / genetics*
  • Respiratory Distress Syndrome, Newborn / mortality
  • Respiratory Distress Syndrome, Newborn / surgery
  • Sequence Analysis, DNA


  • ABCA3 protein, human
  • ATP-Binding Cassette Transporters
  • Genetic Markers