Single ABCA3 mutations increase risk for neonatal respiratory distress syndrome.

Abstract

BACKGROUND AND OBJECTIVE:

Neonatal respiratory distress syndrome (RDS) due to pulmonary surfactant deficiency is heritable, but common variants do not fully explain disease heritability.

METHODS:

Using next-generation, pooled sequencing of race-stratified DNA samples from infants ≥34 weeks' gestation with and without RDS (n = 513) and from a Missouri population-based cohort (n = 1066), we scanned all exons of 5 surfactant-associated genes and used in silico algorithms to identify functional mutations. We validated each mutation with an independent genotyping platform and compared race-stratified, collapsed frequencies of rare mutations by gene to investigate disease associations and estimate attributable risk.

RESULTS:

Single ABCA3 mutations were overrepresented among European-descent RDS infants (14.3% of RDS vs 3.7% of non-RDS; P = .002) but were not statistically overrepresented among African-descent RDS infants (4.5% of RDS vs 1.5% of non-RDS; P = .23). In the Missouri population-based cohort, 3.6% of European-descent and 1.5% of African-descent infants carried a single ABCA3 mutation. We found no mutations among the RDS infants and no evidence of contribution to population-based disease burden for SFTPC, CHPT1, LPCAT1, or PCYT1B.

CONCLUSIONS:

In contrast to lethal neonatal RDS resulting from homozygous or compound heterozygous ABCA3 mutations, single ABCA3 mutations are overrepresented among European-descent infants ≥34 weeks' gestation with RDS and account for ~10.9% of the attributable risk among term and late preterm infants. Although ABCA3 mutations are individually rare, they are collectively common among European- and African-descent individuals in the general population.

• Authors: Jennifer A Wambach, Daniel J Wegner, Kelcey Depass, Hillary Heins, Todd E Druley, Robi D Mitra, Ping An, Qunyuan Zhang, Lawrence M Nogee, F Sessions Cole, Aaron Hamvas
• Journal: Pediatrics (Pediatrics) Vol. 130 Issue 6 Pg. e1575-82 (Dec 2012) ISSN: 1098-4275 [Electronic] United States
• PMID: 23166334 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ABCA3 protein, human
• ATP-Binding Cassette Transporters
• Pulmonary Surfactant-Associated Protein C
• SFTPC protein, human
• 1-Acylglycerophosphocholine O-Acyltransferase
• Lpcat1 protein, human
• Choline-Phosphate Cytidylyltransferase
• PCYT1B protein, human
• Diacylglycerol Cholinephosphotransferase

Topics

• 1-Acylglycerophosphocholine O-Acyltransferase (genetics)
• ATP-Binding Cassette Transporters (genetics)
• Black or African American (genetics)
• Choline-Phosphate Cytidylyltransferase (genetics)
• Cohort Studies
• Diacylglycerol Cholinephosphotransferase (genetics)
• Exome (genetics)
• Gene Expression Regulation (genetics)
• Genetic Association Studies
• Genetic Predisposition to Disease (ethnology, genetics)
• Gestational Age
• Heterozygote
• Homozygote
• Humans
• Infant, Newborn
• Mutation
• Pulmonary Surfactant-Associated Protein C (genetics)
• Respiratory Distress Syndrome, Newborn (ethnology, genetics)
• Risk
• White People (genetics)