Rationale: Mutations in genes encoding proteins important in the function and metabolism of pulmonary surfactant are recognized causes of lung disease. Clinical genetic testing is available for these disorders, but children with phenotypes consistent with surfactant dysfunction and no identifiable mutations in the known causative genes have been reported.
Objectives: To identify the mechanism(s) for lung disease in two children with the phenotype of surfactant dysfunction who had negative testing in clinical laboratories for gene mutations causing surfactant dysfunction.
Methods: Amplicons spanning multiple exons of candidate genes were generated by polymerase chain reaction and sequenced.
Measurements and main results: A 4,335-base deletion that included all of exon 12 of the gene encoding member A3 of the adenosine triphosphate-binding cassette transporter was identified in a full-term infant with respiratory failure. A 333-base deletion involving part of exon 4 and the adjacent intron of the gene encoding surfactant protein C was identified in a child with interstitial lung disease.
Conclusions: Large deletions are a cause of surfactant dysfunction disorders and may need to be sought for specifically in children whose phenotypes suggest these syndromes but in whom clinical genetic testing is unrevealing.