Genotype-phenotype correlations for infants and children with ABCA3 deficiency

Area of Science:

• Genetics
• Pulmonology
• Biochemistry

Background:

• Recessive mutations in ATP-binding cassette transporter A3 (ABCA3) are a known cause of lethal neonatal respiratory failure and childhood interstitial lung disease.
• The majority of ABCA3 mutations identified to date are private, indicating a need for comprehensive genotype-phenotype correlation studies.

Purpose of the Study:

• To establish genotype-phenotype correlations for individuals with recessive ABCA3 mutations.
• To investigate the relationship between specific ABCA3 mutation classifications and clinical presentation and outcomes.

Main Methods:

• A retrospective review of published and unpublished ABCA3 sequence and phenotype data was conducted.
• Data were collected from prospective genetic studies of symptomatic infants and children at Washington and Johns Hopkins Universities.
• Mutations were categorized as 'null' (frameshift, nonsense) or 'other' (missense, splice site, indel), and outcomes were compared across genotypes (null/null, null/other, other/other).

Main Results:

• 185 infants and children with homozygous or compound heterozygous ABCA3 mutations and lung disease were identified.
• All null/null genotype infants presented with respiratory failure at birth, significantly higher than null/other or other/other genotypes (P=0.00011).
• By one year of age, all null/null infants had died or undergone lung transplantation, compared to 62% of null/other and other/other children (P<0.0001).

Conclusions:

• Genotype-phenotype correlations are significant for ABCA3 mutations.
• Frameshift or nonsense (null) ABCA3 mutations predict neonatal presentation and poor prognosis.
• Missense, splice site, and indel mutations are less consistently associated with presentation age and prognosis, necessitating careful clinical consideration.