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

CPQCC Publication
TitleExome Sequencing of Neonatal Blood Spots and the Identification of Genes Implicated in Bronchopulmonary Dysplasia.
Publication TypeJournal Article
Year of Publication2015
AuthorsLi J, Yu K-H, Oehlert J, Jeliffe-Pawlowski LL, Gould JB, Stevenson DK, Snyder M, Shaw GM, O'Brodovich HM
JournalAm J Respir Crit Care Med
Date Published2015 Sep 01
KeywordsAnimals, Blood Specimen Collection, Bronchopulmonary Dysplasia, Case-Control Studies, Exome, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Haploinsufficiency, Humans, Infant, Infant, Extremely Premature, Infant, Newborn, Infant, Premature, Lung, Male, Mice, Morphogenesis, Neonatal Screening, Sequence Analysis, DNA, Twins, Dizygotic, Twins, Monozygotic, Wnt Signaling Pathway

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.

Alternate JournalAm. J. Respir. Crit. Care Med.
PubMed ID26030808
PubMed Central IDPMC4595691
Grant List5P50HG00773502 / HG / NHGRI NIH HHS / United States
5U01HL10739304 / HL / NHLBI NIH HHS / United States
1P50HG00773501 / HG / NHGRI NIH HHS / United States
R01 HL122887 / HL / NHLBI NIH HHS / United States
RC2 HL101748 / HL / NHLBI NIH HHS / United States