Genotype–Phenotype Correlations for Infants and Children with ABCA3 Deficiency

Abstract

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To determine genotype-phenotype correlations for recessive ABCA3 mutations.Methods: We reviewed all published and unpublished ABCA3 sequence and phenotype data from our prospective genetic studies of symptomatic infants and children at Washington and Johns Hopkins Universities.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.

Management of suspected monogenic lung fibrosis in a specialised centre

“…Biallelic ABCA3 mutations were first reported in children with ILD and are associated with adult ILD in cases of biallelic missense and nonsense mutations [78,81,82]. Biallelic ABCA3 mutations and heterozygous SFTPC mutations in adults may have a similar clinical and radiological presentation [83,84].…”

Increased Risk of Interstitial Lung Disease in Children with a Single R288K Variant of ABCA3

“…Some variants lead to rare but well-characterized chronic children's interstitial lung disease with a firm histopathological pattern including desquamative interstitial pneumonitis or nonspecific interstitial pneumonitis (14,15). The ABCA3 variant R288K (c.863G>A) has been previously associated with pediatric respiratory disease (6) and a single copy was three-to four-fold enriched among the European-descent infants with neonatal respiratory distress (9,16,17), although it is predicted to be benign and tolerated by the algorithms Polyphen and SIFT.…”

Interstitial Lung Disease in Children Younger Than 2 Years

“…1,[7][8][9] Similarly, idiopathic pulmonary fibrosis, the most common and severe of the idiopathic interstitial pneumonias in adults, 10,11 is not found in children. On the other hand, there are forms of ILD that are unique to infants and children younger than 2 years of age, 7 hence the use of adult terminology and classification does not adequately address pediatric entities.…”

“…Mutations within ABCA3 are the most common genetic cause of respiratory failure in fullterm infants. 9,67 In fact, affected infants present in the neonatal period with severe and progressive RDS despite medical treatment. 68 There is a genotype-phenotype correlation; patients homozygous for severe mutations invariably have a neonatal presentation and death in the first year of life, whereas milder mutations permit prolonged survival.…”

“…68 There is a genotype-phenotype correlation; patients homozygous for severe mutations invariably have a neonatal presentation and death in the first year of life, whereas milder mutations permit prolonged survival. 9 However, ABCA3 mutations have been identified also in older children and even young adults with ILD, usually with DIP. 69 Distinctive ultrastructural abnormalities observed in the alveolar type II cells of patients with ABCA3 mutations include small, markedly abnormal lamellar bodies with densely packed phospholipid membranes and electron-dense inclusions.…”