Population-based Frequency and Functional Characterization of a Pathogenic ABCA3 Intronic Variant Associated With Lethal Neonatal RDS

ATP-binding cassette member A3 (ABCA3) transports phospholipids required for surfactant assembly into lamellar bodies (LBs) of alveolar type-II cells. Biallelic pathogenic ABCA3 variants are the most common monogenic cause of progressive, lethal neonatal respiratory failure (NRF) in term infants. ABCA3 mutant proteins can disrupt intracellular processing and trafficking to the LBs or impair phospholipid transport into the LBs. A deep intronic ABCA3 variant (c.3863-98C>T) identified in term infants, frequently of Colombian-descent, with lethal NRF causes aberrant splicing by creating a new donor site and introducing an in-frame 150 base pair (bp) cryptic exon between exons 25 and 26. Data from 1000 Genomes suggest a minor allele frequency (MAF) of this variant as 0.042 among Colombian-descent adults. Functional characterization of this intronic variant is limited as cell-based model systems typically use coding DNA (cDNA) that does not include intronic regions.