The ATP-binding cassette transporter member A3 (ABCA3) is a lipid transporter with a critical function in pulmonary surfactant biogenesis. Biallelic loss-of-function mutations in ABCA3 result in severe surfactant deficiency leading to neonatal respiratory failure with death in the first year of life. Herein, we describe a newborn with severe respiratory distress at birth progressing to respiratory failure requiring transplant. This patient was found to have a maternally inherited frameshift loss-of-function ABCA3 mutation and a paternally inherited synonymous variant in ABCA3 predicted to create a cryptic splice site. Additional studies showed reduced ABCA3 expression in hyperplastic alveolar epithelial type II cells and lamellar body alterations characteristic of ABCA3 deficiency, leading to a diagnosis of autosomal recessive ABCA3-related pulmonary surfactant dysfunction. This case highlights the need for an integrated, comprehensive approach for the diagnosis of inherited diseases when in silico modeling is utilized in the interpretation of key novel genetic mutations.
Bibliographical noteFunding Information:
We thank the family for allowing us to publish their case. The control nontransplanted donor lung was obtained from LifeCenter Organ Donor Network (Cincinnati, OH) in collaboration with Francis X. McCormack, MD (University of Cincinnati, Cincinnati, OH). This study was also supported by services from the Pathology Research Core shared facility in the Cincinnati Children’s Research Foundation with specific acknowledgment of the assistance of Robin Sams.
© 2020 Oltvai et al. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License, which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.
- progressive pulmonary function impairment
- respiratory insufficiency
PubMed: MeSH publication types
- Journal Article
- Research Support, Non-U.S. Gov't