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Single mutations in one gene increased risk for neonatal respiratory distress syndrome
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Single mutations in the ABCA3 gene may play a significant role in the development of neonatal respiratory distress syndrome in infants born at or near full term, according to study results published online.
Jennifer A. Wambach, MD, assistant professor of pediatrics at Washington University School of Medicine, St. Louis, and colleagues evaluated five genes involved in metabolizing lung surfactant. The researchers used DNA samples from 513 infants of African and European descent, with and without respiratory distress.
Jennifer A. Wambach
Infants of European descent with respiratory distress were more likely to have a single mutation in ABCA3 compared with the infants without breathing problems, the researchers said. Infants of African descent had similar issues when they had a single ABCA3 mutation, but this difference did not reach statistical significance. The researchers found similar findings in a smaller sample of babies with severe respiratory distress.
“We found that mutations in ABCA3 account for about 10% of respiratory disease in babies born near their due dates who we typically think should have mature lungs and breathe normally,” Wambach told Infectious Diseases in Children. “We have known that neonatal RDS is a heritable disease, but this is the first gene to account for a significant proportion of disease among term or near-term infants.”
The researchers said studies such as these could lead to targeted medical therapies toward the abnormal protein resulting from these mutations.
Disclosure: Some of the researchers reported receiving funding for this research from NIH.
Jennifer A. Wambach, MD, can be reached at Washington University School of Medicine, 8th Floor NWT, Box 8116, St. Louis, MO 63110; Email: Wambach_J@kids.wustl.edu.
Perspective
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Christiane E.L. Dammann, MD
The major finding is that even in a population at reduced risk for RDS (due to later gestational age), single ABCA3 mutations account for 11% of RDS in late preterm infants of European descent. This novel finding suggests that homozygous or compound heterozygous ABCA3 mutations are associated with a progressive and lethal form of RDS respiratory distress due to reduced phosphatidylcholine content and surface tension lowering function of pulmonary surfactant. Rare, deleterious, highly penetrant variants at multiple gene loci have been implicated in the heritability of complex diseases. The approach Wambach and colleagues have chosen has been shown to be successful for the discovery of gene loci with excess, rare mutations associated with complex diseases in larger sized cohorts.
Despite the limitations of the study (eg, cannot exclude epigenetic, environmental, or developmental factors), this approach can help explain why common variants of diseases do not fully explain disease heritability. The group ended on a note that “next generation, exome, or whole genome sequencing methods would even permit even more comprehensive genetic discovery of mutations that contribute to RDS heritability.” This approach would certainly need to be supplemented by gene-environment and gene-gene-interaction studies that take genetic makeup and environmental risk factors (eg, infection) into account.
Finally, we are left with the question of applicability to the clinical setting. If an obstetrician had knowledge of genetic patterns when considering the need for a late preterm delivery, it might influence his/her decision. However, the neonatologist would still administer exogenous surfactant based on clinical presentation, not on genetic information. Still, these data always contribute to an improved understanding of disease mechanisms, which will be enhanced if future genetic epidemiologic studies are supplemented with measurement of biologically relevant RNA or protein data at systemic and organ levels.
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