Single ABCA3 mutations increase risk for neonatal respiratory distress syndrome

Jennifer A. Wambach, Daniel J. Wegner, Kelcey DePass, Hillary Heins, Todd E. Druley, Robi D. Mitra, Ping An, Qunyuan Zhang, Lawrence Nogee, F. Sessions Cole, Aaron Hamvas

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalPediatrics
Volume130
Issue number6
DOIs
StatePublished - Dec 2012

Fingerprint

Newborn Respiratory Distress Syndrome
Mutation
Population
Pyridinolcarbamate
Pulmonary Surfactants
Pregnancy
Syndrome
Mutation Rate
Premature Infants
Surface-Active Agents
Computer Simulation
Genes
Exons
Descent
DNA

Keywords

  • Genetic association studies
  • Neonatal respiratory distress syndrome
  • Newborn
  • Respiratory distress syndrome

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Arts and Humanities (miscellaneous)

Cite this

Wambach, J. A., Wegner, D. J., DePass, K., Heins, H., Druley, T. E., Mitra, R. D., ... Hamvas, A. (2012). Single ABCA3 mutations increase risk for neonatal respiratory distress syndrome. Pediatrics, 130(6). https://doi.org/10.1542/peds.2012-0918

Single ABCA3 mutations increase risk for neonatal respiratory distress syndrome. / Wambach, Jennifer A.; Wegner, Daniel J.; DePass, Kelcey; Heins, Hillary; Druley, Todd E.; Mitra, Robi D.; An, Ping; Zhang, Qunyuan; Nogee, Lawrence; Cole, F. Sessions; Hamvas, Aaron.

In: Pediatrics, Vol. 130, No. 6, 12.2012.

Research output: Contribution to journalArticle

Wambach, JA, Wegner, DJ, DePass, K, Heins, H, Druley, TE, Mitra, RD, An, P, Zhang, Q, Nogee, L, Cole, FS & Hamvas, A 2012, 'Single ABCA3 mutations increase risk for neonatal respiratory distress syndrome', Pediatrics, vol. 130, no. 6. https://doi.org/10.1542/peds.2012-0918
Wambach JA, Wegner DJ, DePass K, Heins H, Druley TE, Mitra RD et al. Single ABCA3 mutations increase risk for neonatal respiratory distress syndrome. Pediatrics. 2012 Dec;130(6). https://doi.org/10.1542/peds.2012-0918
Wambach, Jennifer A. ; Wegner, Daniel J. ; DePass, Kelcey ; Heins, Hillary ; Druley, Todd E. ; Mitra, Robi D. ; An, Ping ; Zhang, Qunyuan ; Nogee, Lawrence ; Cole, F. Sessions ; Hamvas, Aaron. / Single ABCA3 mutations increase risk for neonatal respiratory distress syndrome. In: Pediatrics. 2012 ; Vol. 130, No. 6.
@article{cd32b639fdd74b7999a4180ead02e94e,
title = "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.",
keywords = "Genetic association studies, Neonatal respiratory distress syndrome, Newborn, Respiratory distress syndrome",
author = "Wambach, {Jennifer A.} and Wegner, {Daniel J.} and Kelcey DePass and Hillary Heins and Druley, {Todd E.} and Mitra, {Robi D.} and Ping An and Qunyuan Zhang and Lawrence Nogee and Cole, {F. Sessions} and Aaron Hamvas",
year = "2012",
month = "12",
doi = "10.1542/peds.2012-0918",
language = "English (US)",
volume = "130",
journal = "Pediatrics",
issn = "0031-4005",
publisher = "American Academy of Pediatrics",
number = "6",

}

TY - JOUR

T1 - Single ABCA3 mutations increase risk for neonatal respiratory distress syndrome

AU - Wambach, Jennifer A.

AU - Wegner, Daniel J.

AU - DePass, Kelcey

AU - Heins, Hillary

AU - Druley, Todd E.

AU - Mitra, Robi D.

AU - An, Ping

AU - Zhang, Qunyuan

AU - Nogee, Lawrence

AU - Cole, F. Sessions

AU - Hamvas, Aaron

PY - 2012/12

Y1 - 2012/12

N2 - 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.

AB - 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.

KW - Genetic association studies

KW - Neonatal respiratory distress syndrome

KW - Newborn

KW - Respiratory distress syndrome

UR - http://www.scopus.com/inward/record.url?scp=84870499614&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84870499614&partnerID=8YFLogxK

U2 - 10.1542/peds.2012-0918

DO - 10.1542/peds.2012-0918

M3 - Article

C2 - 23166334

AN - SCOPUS:84870499614

VL - 130

JO - Pediatrics

JF - Pediatrics

SN - 0031-4005

IS - 6

ER -