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Am J Respir Crit Care Med. 2015 Sep 1;192(5):589-96. doi: 10.1164/rccm.201501-0168OC.

Exome Sequencing of Neonatal Blood Spots and the Identification of Genes Implicated in Bronchopulmonary Dysplasia.

Author information

1
1 Department of Genetics, Center for Genomics and Personalized Medicine.
2
2 Biomedical Informatics Program, and.
3
3 Department of Pediatrics, Stanford University School of Medicine, Stanford, California.
4
4 California Department of Public Health, Richmond, California; and.
5
5 Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California.

Abstract

RATIONALE:

Bronchopulmonary dysplasia (BPD), a prevalent severe lung disease of premature infants, has a strong genetic component. Large-scale genome-wide association studies for common variants have not revealed its genetic basis.

OBJECTIVES:

Given the historical high mortality rate of extremely preterm infants who now survive and develop BPD, we hypothesized that risk loci underlying this disease are under severe purifying selection during evolution; thus, rare variants likely explain greater risk of the disease.

METHODS:

We performed exome sequencing on 50 BPD-affected and unaffected twin pairs using DNA isolated from neonatal blood spots and identified genes affected by extremely rare nonsynonymous mutations. Functional genomic approaches were then used to systematically compare these affected genes.

MEASUREMENTS AND MAIN RESULTS:

We identified 258 genes with rare nonsynonymous mutations in patients with BPD. These genes were highly enriched for processes involved in pulmonary structure and function including collagen fibril organization, morphogenesis of embryonic epithelium, and regulation of Wnt signaling pathway; displayed significantly elevated expression in fetal and adult lungs; and were substantially up-regulated in a murine model of BPD. Analyses of mouse mutants revealed their phenotypic enrichment for embryonic development and the cyanosis phenotype, a clinical manifestation of BPD.

CONCLUSIONS:

Our study supports the role of rare variants in BPD, in contrast with the role of common variants targeted by genome-wide association studies. Overall, our study is the first to sequence BPD exomes from newborn blood spot samples and identify with high confidence genes implicated in BPD, thereby providing important insights into its biology and molecular etiology.

KEYWORDS:

bronchopulmonary dysplasia; chronic lung disease; exome sequencing; genetic predisposition to disease; premature

PMID:
26030808
PMCID:
PMC4595691
DOI:
10.1164/rccm.201501-0168OC
[Indexed for MEDLINE]
Free PMC Article

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